Immunogenicity and safety of CoronaVac in children in an immuno-bridging phase 3 clinical trial

Immunogenicity and safety of CoronaVac in children in an immuno-bridging phase 3 clinical trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Immunogenicity and safety of CoronaVac in children in an immuno-bridging phase 3 clinical trial Weining Meng, Qin Sun, Ying Xie, Yanqing Zhao, Jialei Hu, Xianghong Wu, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3251584/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Several clinical trials demonstrated that CoronaVac had favorable efficacy and immunogenicity in adults and children. This phase 3, open-label, immuno-bridging clinical trial assessed the superior immunogenicity of CoronaVac in Chinese children aged 3–11 years compared to Brazilian adults aged 18–26 years, and its non-inferiority in Chinese children compared to overseas children (NCT05137418). A sample size of 1000 healthy children aged 3–11 years were enrolled in China. Two doses of CoronaVac were given 28 days apart. Superiority and non-inferiority analysis were conducted by assessing the neutralizing antibodies titers against SARS-CoV-2. The geometric mean titer (GMT) of neutralizing antibodies in Chinese children on day 28 post second dose vaccination was 198.47 (95%CI 189.44-207.93), superior to that of the Brazilian adults (62.52, 95%CI 54.99–71.08) with the adjusted GMT ratio of 3.18 (95%CI 2.85–3.54); and it was non-inferior compared to the overseas children (202.58, 95%CI 166.29–246.80) with the adjusted GMT ratio of 0.98 (95%CI 0.85–1.13) and seroconversion rate difference of 0.00% (95%CI -0.44-2.58). Most adverse reactions were mild and moderate. All of the serious adverse events (SAEs) were considered unrelated to vaccination. CoronaVac showed good immunogenicity and safety in children aged 3–11 years. The results suggested that CoronaVac could have favorable protection against COVID-19 in children. Biological sciences/Immunology/Vaccines/Inactivated vaccines Biological sciences/Immunology Figures Figure 1 Figure 2 Introduction Coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has been spreading around the world 1 , resulting in large morbidity and mortality to people of all ages. Although most children experienced the illness with less severity and fewer deaths were reported compared to adults, critical cases such as multisystem inflammatory syndrome in children (MIS-C) kept appearing despite the low incidence, especially in children with underlying medical conditions 2,3,4 . Children play an important role in the transmission of the disease in communities or households 5,6 . Thus, effective vaccination could not only protect children from severe complications, but also help to achieve herd immunity in all age groups 7,8 . CoronaVac is an inactivated SARS-CoV-2 vaccine developed by Sinovac Life Sciences (Beijing, China). Three phase 1/2 clinical trials have already shown that CoronaVac has good safety, tolerability and immunogenicity in children, adults and older people 9,10,11 . A phase 3 clinical trial in Brazilian adults showed favorable efficacy of CoronaVac in preventing COVID-19 after 2 doses of vaccination 12 . On February 5, 2021, CoronaVac was approved for conditional marketing in China by the National Medical Products Administration (NMPA) (approval number: 2021S00156, 2021S00157). It was recommended for use in people aged 3 years and above and was one of the most widely used COVID-19 vaccine in China. CoronaVac was also listed for emergency use by World Health Organization (WHO) in people aged 18 years and above on June 1, 2021, and was extended to children aged 3–17 years on November 2, 2022 13 . Although multiple studies on the protective efficacy of CoronaVac have been obtained abroad, the protective effect in Chinese children is still lacking in the evaluation. Due to strict epidemic control measures in 2021, there were only a few cases of COVID-19 in China, and it was impossible to conduct large-scale efficacy studies. No surrogate endpoint of COVID-19 vaccine has been established; however, previous studies had demonstrated that vaccine efficacy might be positively correlated to neutralizing antibodies levels 14,15 . To further provide immunogenicity and safety data of CoronaVac in Chinese children, this phase 3 immuno-bridging clinical trial was initiated in November 2021. The objectives of this study were to assess the superior immunogenicity of CoronaVac in Chinese children aged 3–11 years compared to Brazilian adults aged 18–26 years, and the immunogenicity non-inferiority in Chinese children compared to overseas children. The cross-neutralization effect would also be evaluated considering the prevalence of the SARS-CoV-2 variants. Results Baseline Demographics In November 2021, 1014 children were screened and 1000 were enrolled, including 502 aged 3–5 years and 498 aged 6–11 years. All the participants received the first dose vaccination and were included in the Full analysis set (FAS) and Safety set (SS)/Safety set of first dose (SS1). 983 participants completed the second dose vaccination, 867 of whom were included in the PPS for immunogenicity evaluation. In the control group, 327 Brazilian adults and 145 overseas children with serum samples pre- and post-immunization were included in PPS. The age of the Chinese children and overseas children were all of 3–11 years, and the mean age of the Brazilian adults was 24.98 years old. In the PPS, no Chinese children and overseas children were seropositive pre-vaccination, and 296 (90.52%) Brazilian adults were seronegative pre-vaccination (Fig. 1 & Table 1 ). Table 1 Baseline characteristics of study participants (PPS) Chinese children Brazilian adults Overseas children No. of participants 867 327 145 Male sex, no. (%) 432(49.83) 84(25.69) 72(49.66) Mean Age in years, (interquartile range) 6.67(2.22) 24.98(1.51) 7.55(4.70) 3–5 years, no. (%) 404(46.60) - 52(35.86) 6–11 years, no. (%) 463(53.40) - 93(64.14) Seronegative at baseline, no. (%) 867(100.00) 296(90.52) 145(100.00) Immunogenicity in the Chinese children At 28 days after the second dose, the GMT of neutralizing antibodies in Chinese children aged 3–5 years and 6–11 years were 220.60 and 180.98, and the GMC of anti-SARS-CoV-2 S antibodies were 1211.66 and 821.26, respectively (Supplementary Table 1). For baseline seronegative participants, the GMT of neutralizing antibodies at 28 days after the second dose in the Chinese children, Brazilian adults and overseas children were 198.47 (95%CI 189.44-207.93), 62.52 (95%CI 54.99–71.08) and 202.58 (95%CI 166.29–246.80), respectively. The seroconversion rates in the Chinese children, Brazilian adults and overseas children were 100% (95%CI 99.58–100.00), 97.64% (95%CI 95.19–99.04), and 100% (95%CI 97.49–100.00), respectively. All the Chinese children turned seropositive at 28 days after the second dose. According to the covariance model analysis, the GMT of neutralizing antibodies in the Chinese children was superior to that of the Brazilian adults, with an adjusted GMT ratio of 3.18 (95%CI 2.85–3.54); while the GMT of neutralizing antibodies in the Chinese children was non-inferior to that of the overseas children, with an adjusted GMT ratio of 0.98 (95%CI 0.85–1.13) (P = 0.7727). The seroconversion rate was also insignificant between the Chinese children and overseas children, with a rate difference of 0.00% (95%CI -0.44-2.58) (Table 2 & Supplementary Table 2 and Table 3 ). Table 2 Immunogenicity analysis between Chinese children and Brazilian adults/overseas children in the seronegative participants at baseline (PPS) Chinese children (N = 867) Brazilian adults (N = 296) Overseas children (N = 145) Pre-vaccination GMT (95%CI) 2.03 2.03 2.03 28 days after the second dose # GMT (95%CI) 198.47 (189.44,207.93) 62.52 (54.99,71.08) 202.58 (166.29,246.80) Adjusted GMT 1 , (95%CI) 198.48 (187.84, 209.72) 62.5 (56.89, 68.69) 202.57 (178.08, 230.44) Adjusted GMT ratio 2 , (95%CI) - 3.18 (2.85, 3.54) 0.98 (0.85, 1.13) Seroconversion rate, %, (95%CI) 100 (99.58, 100.00) 97.64 (95.19, 99.04) 100 (97.49, 100.00) Rate difference 3 , %, (95%CI) - - 0.00 (-0.44, 2.58) Abbreviations: GMT, geometric mean titer; 95%CI, 95% confidence interval; Seroconversion was defined as a titer of neutralizing antibodies ≥ 1:8 post-vaccination in subjects with seronegative neutralizing antibodies pre-vaccination. # For Brazilian adults, the serum samples were collected at 14 days after the second dose. 1 Calculated by covariance analysis model, adjusting for pre-vaccination neutralizing antibody titers. 2 Ratio values presented were those of Chinese children versus Brazilian adults, or Chinese children versus overseas children. 3 Rate differences presented was of Chinese children versus overseas children. At 6 months after the second dose, the GMT of neutralizing antibodies in children aged 3–5 years and 6–11 years were 19.73 and 9.22, respectively, and the seropositive rates were 94.87% and 64.64%, respectively (Supplementary Table 1). Cross-neutralization against other SARS-CoV-2 variants in Chinese children Before immunization, neutralizing antibodies of all the participants were negative against the variant strains. At 28 days after the second dose, the seropositive rates of neutralizing antibodies in the 3–5 years group against Gamma, Delta and Omicron strains were 99.33%, 97.33% and 17.33%, respectively, and in the 6–11 years group were 99.33%, 96.00% and 8.67%, respectively. At 6 months after the second dose, the seropositive rates dropped significantly, with the neutralizing antibodies in the 3–5 years group against Gamma, Delta and Omicron strains were 73.44%, 40.63% and 2.68%, respectively, and in the 6–11 years group were 30.33%, 23.01% and 0.21%, respectively. The neutralizing antibodies level of the Omicron strain at every timepoint post-vaccination was significantly lower than those of the prototype strain and other two variants (P < 0.0001). (Fig. 2 ) Safety Safety analysis was conducted in SS subset. The incidences of overall ARs were generally similar among the two groups- 42.83% in the 3–5 years group and 35.14% in the 6–11 years group, respectively. Most of the ARs occurred within 7 days post-vaccination and were mild and moderate. Grade 3 adverse reactions were fever (1.90%) and cough (0.30%). Two most common systemic adverse reactions were cough (16.33% in the 3–5 years group and 13.45% in the 6–11 years group) and fever (11.95% in the 3–5 years group and 12.65% in the 6–11 years group). The most frequently reported local adverse reaction was injection-site pain (16.14% in the 3–5 years group and 13.05% in the 6–11 years group). From day 0 to six months after the second dose, 31 SAEs were reported by 13 participants. All the SAEs were deemed unrelated to the vaccine. (Table 3 ) Table 3 Adverse reactions from day 0 to 28 days after the second dose in Chinese children 3–5 years (N = 502) 6–11 years (N = 498) Total (N = 1000) Total 215(42.83) 175(35.14) 390(39.00) Local reaction (injection site) 148(29.48) 131(26.31) 279(27.90) Pain 81(16.14) 65(13.05) 146(14.60) Pruritus 15(2.99) 9(1.81) 24(2.40) Induration 9(1.79) 10(2.01) 19(1.90) Swelling 8(1.59) 4(0.80) 12(1.20) Redness 4(0.80) 5(1.00) 9(0.90) Systemic reaction 98(19.52) 78(15.66) 176(17.60) Cough 82(16.33) 67(13.45) 149(14.90) Fever 60(11.95) 63(12.65) 123(12.30) Vomiting 23(4.58) 11(2.21) 34(3.40) Rhinorrhea 20(3.98) 12(2.41) 32(3.20) Headache 5(1.00) 18(3.61) 23(2.30) Fatigue 7(1.39) 14(2.81) 21(2.10) Decreased appetite 9(1.79) 10(2.01) 19(1.90) Nausea 6(1.20) 10(2.01) 16(1.60) Diarrhea 8(1.59) 7(1.41) 15(1.50) Allergic reaction 2(0.40) 2(0.40) 4(0.40) Discussion This was the first study to evaluate the immunogenicity of CoronaVac in children compared with that in adults. The immunogenicity results showed that the ratio of adjusted GMTs (95% CI) between the Chinese children aged 3–11 years and the Brazilian adults aged 18–26 years was 3.18, the lower limit of 95%CI was 2.85, which was higher than the superiority cut-off value of 3/2. Thus, the superior immunogenicity was claimed. According to the results of phase 3 clinical trial in adults in Brazil, the efficacy of CoronaVac against symptomatic COVID-19 was 50.7% and against severe symptoms was 100%. It is suggested in this study that the efficacy of CoronaVac in children population was favorable. Through the non-inferiority comparation, it was found that Chinese children and overseas children at the same age could produce similar levels of neutralizing antibodies after vaccination. The overseas children in the multi-center phase III clinical trial were from countries of South Africa, Chile, Malaysia and the Philippines, who were with different ethnicities. The results could indicate that CoronaVac has good immunogenicity cross different ethnic groups. Stratified by age, both neutralizing antibodies and anti-SARS-CoV-2 S antibodies levels increased with decreasing age (Supplementary Table 1), which is consistent with the results from a previous children and adolescents study of CoronaVac 11 . These results further support that SARS-CoV-2 infections may result in less severe symptoms among children and adolescents compared to adults 16 . The superiority evaluation of neutralizing antibodies was conducted at different timepoints due to different vaccination schedules in the two groups—day 0, 28 immunization schedule for Chinese children and day 0, 14 schedule for Brazilian adults. The superiority results also suggest that the day 0, 28 vaccination schedule might achieve better immune protection 17,18 . In baseline seropositive Brazilian adults, CoronaVac induced higher neutralizing antibodies levels compared to baseline seronegative ones (find the results in the supplementary). A similar phenomenon had also been found in the SARS-CoV-2 mRNA vaccine: a rapid immune response could be elicited by a single dose of mRNA vaccine in seropositive participants; their post-vaccination antibody titers were similar or above those of seronegative participants who received two doses of vaccination 19,20 . However, further research is needed to investigate if this stronger immune response could be elicited in children, which can help to develop better vaccination strategies. Long-term immunogenicity at 6 months after the second dose declined significantly: the neutralizing antibody GMTs (prototype strain) decreased from 220.60 to 19.73 in the 3–5 years group and from 180.98 to 9.22 in the 6–11 years group. Similar declines were also present against the variant strains. What’s more, the cross-neutralization results indicated a weak immune response against the Omicron strain with two doses of CoronaVac, which suggested the necessity of booster vaccination. The safety data showed that CoronaVac was well tolerated in children aged 3–11 years. The safety results in this study were comparable with the results in the Phase 1/2 pediatric clinical study in the same age group 11 . Most adverse reactions resolved in a few days with mild and moderate symptoms, and none of the SAE was deemed related to the vaccine. Method Study design and participants The study was a single-center, open-label and immuno-bridging clinical trial to evaluate the immunogenicity and safety of CoronaVac in Sheyang county, Jiangsu province, China. A total of 1000 participants were planned to be enrolled, including 500 children aged 3–5 years and 500 children aged 6–11 years. Main exclusion criteria included history of confirmed infection of SARS-CoV-2, contact history with someone infected with SARS-CoV-2 within 14 days prior to study entry, vaccination history of COVID-19 vaccine, and allergy to any vaccine component (for full inclusion and exclusion criteria, see the supplementary). Informed consents need to be signed by the guardians, and children aged 8 years and above should also provide written assents before enrollment. The study protocol and informed consent form were approved by the ethics committee of Jiangsu Center for Disease Control and Prevention (CDC). This trial was conducted in compliance with the Declaration of Helsinki, Good Clinical Practice, and Chinese regulatory requirements. The study was registered with ClinicalTrials.gov (NCT05137418). To conduct the immunogenicity superiority evaluation, the back-up serum samples of the phase III clinical trial in Brazil (clinical trial.gov NCT04456595), which were paired of pre- and post-immunization with sufficient volume for testing, were selected in order of numbering. The study was established in 2020 and designed as randomized, double-blind to evaluate the efficacy of CoronaVac with the vaccination schedule of 0,14 days in Brazilian adults aged 18–59 years. 12 The serum samples were collected at 14 days after the second dose. For the non-inferiority evaluation, serum samples from overseas children in the multi-center phase III clinical trial (clinical trial.gov NCT04992260) were used. The serum samples were also paired of pre- and post-immunization with sufficient volume for testing, and selected in order of numbering. The study was conducted in children and adolescents from Chile, South Africa, Malaysia and the Philippines in 2021, for assessing the efficacy of CoronaVac in children aged 6 months to 17 years old. The overseas children received 2 does of CoronaVac in 28 days apart and collected the serum samples at 28 days after the second dose. In order to control the bias in vaccine immunogenicity caused by the large age span, the serum samples of Brazilian adults aged 18–26 years were used for superiority evaluation, and the samples of overseas children aged 3–11 years were used for non-inferiority evaluation. Study vaccine CoronaVac was an inactivated SARS-CoV-2 vaccine and was created from African green monkey kidney cells (Vero cells), which had been inoculated with SARS-CoV-2 ancestral strain (CZ02). The SARS-CoV-2 strain was then harvested, inactivated, concentrated, purified, and adsorbed onto aluminum hydroxide. The vaccine was prepared in a Good Manufacturing Practice-accredited facility of Sinovac, which was periodically inspected by the NMPA committee for compliance. CoronaVac was packaged in a pre-filled syringe with 600 SU (3µg) of SARS-CoV-2 antigen per dose (0.5 mL/syringe). Participants assignment Participants were assigned into two groups according to the age of 3–5 years or 6–11 years. Every participant was assigned an open-label vaccine number in chronological order in each group and received the vaccine with the same number. Study procedure After the informed consent forms signed and dated by participants and/or their guardians, and physical examination and inclusion and exclusion criteria screening were passed, participants would be enrolled into the study. Participants received 2 doses of CoronaVac intramuscularly in the deltoid region with an interval of 28 days. About 3.5ml venous blood were collected from all participants pre-vaccination, 28 days and 6 months post second-dose vaccination, respectively. The immunologic assays of the neutralizing antibodies of all the serum samples were conducted by China National Institutes for Food and Drug Control (CNIFDC). After each vaccination, participants were observed for 30 minutes for immediate adverse reactions (ARs, adverse events with reasonable causal relationship with study vaccine). Solicited local adverse events (AEs) (e.g., injection-site pain, induration, swelling) and systemic AEs (e.g., allergic reaction, fever, headache, cough) within 7 days after each dose were required to be recorded on the diary cards by participants or their guardians. Unsolicited AEs occurring within 28 days after each dose were also collected by spontaneous report from the participants combined with the regular visit (which occurred on day 8 and day 28 after each dose). Serious adverse events (SAE) were monitored until 12 months after the second dose and followed-up until resolution if any. The severity of AE was graded according to the China National Medical Products Administration guidelines 21 . The causal association between adverse events and vaccination was determined by site investigators. Immunogenicity assessment The neutralizing antibodies titers against live SARS-CoV-2 (prototype strain CZ01, Gamma strain P.1, Delta strain B.1.167.2, Omicron strain BA.1) were quantified by the micro-cytopathogenic effect assay 22 . The primary immunogenicity endpoint was the geometric mean titer (GMT) of neutralizing antibodies against prototype strain on day 28 after the second dose. Secondary immunogenicity endpoints were seropositivity rate (defined as neutralizing antibodies ≥ 1:8) and seroconversion rate of neutralizing antibodies at 28 days and 6 months after the second dose, and the GMT of neutralizing antibodies at 6 months after full vaccination. Seroconversion was defined as ( 1 ) neutralizing antibodies titers ≥ 1:8 post-vaccination in subjects with seronegative neutralizing antibodies pre-vaccination or ( 2 ) neutralizing antibodies titers increased by 4 times or more post-vaccination in subjects who were seropositive pre-vaccination. The superiority would be claimed if the lower limit of the 95% confidence interval (95% CI) of the adjusted GMT ratio was > 3/2 after adjusting for pre-vaccination neutralizing antibody titers. The non-inferiority would be claimed if ( 1 ) the lower limit of the 95% CI of the adjusted GMT ratio was > 2/3 and ( 2 ) the lower limit of the 95% CI of the seroconversion rate difference was >-5%. Meanwhile, the antibody levels against the Receptor Binding Domain (RBD) of the S protein of the Chinese children at 28 days after the second dose were quantified by using the Roche Anti-SARS-CoV-2 S assay 23 , with the corresponding endpoints of seroconversion rate and geometric mean concentration (GMC). Safety assessment Safety assessment was performed throughout the study. Safety endpoints included ARs within 0–28 days after each dose vaccination, and SAEs following the first dose inoculation to 12 months after the second dose vaccination. Statistical analysis The sample size was determined based on the superiority and non-inferiority design. To achieve 90% power at a two-sided 5% significance level, with logarithmic standard deviation 0.7 (based on previous research results), and assumed the sample size of Brazilian adults was at least 260, we calculated that the sample size was 462 for Chinese children in the superiority design. While in the non-inferiority design comparing serum of overseas children, the sample size of each Chinese and overseas children group was calculated to be 333; meantime, assumed that the seroconversion rate of neutralizing antibodies post-immunization was 90%, the sample size of each group was calculated to be 775. To meet the maximum sample size requirement and a 20% drop-out rate, a total of 1000 Chinese children were included in this trial. GMTs and corresponding 95% CIs were calculated on the basis of standard normal distribution of the log-transformed neutralizing antibodies titer. The adjusted GMTs were calculated by using the covariance analysis model, which took the mean of the log transformed neutralizing antibodies titer after immunization as the dependent variable, the logarithmic GMT before immunization as the covariate, and the group as the fixed effect. Calculate the least squares mean of adjusted GMT ratio (adjusted GMT of Chinese children/ Brazilian adults or overseas children) and corresponding 95%CI for superiority comparison. The 95% CI of seroconversion rate difference were estimated using the Miettnen-Nurminen method. The immunogenicity endpoints were evaluated in the per protocol set (PPS) which included participants who had received 2 doses of CoronaVac and had available antibodies results pre- and post-vaccination. The superiority and non-inferiority evaluation were in the PPS of the participants who were seronegative at baseline. The safety endpoints were evaluated in the safety set (SS) which included participants who received at least 1 dose of CoronaVac. SAS (version 9.4) was used for statistical analysis. Declarations Ethics statement The studies involving human participants were reviewed and approved by ethics committee of Jiangsu Provincial CDC (approval number: JSJK2021-A036-01). The participants and/or their legal guardian provided written informed consent to participate in this study. Data availability statement The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors. Acknowledgements The authors would like to express their thanks to the staff of Jiangsu Provincial CDC and to the local CDCs (Sheyang Center for Disease Control and Prevention) for their efforts in leading the field work for this trial. We would like to express our sincere gratitude to all participants in this study. Author contributions QS, YX and YZ participated in manuscript drafting. YZ, KC, QX, JH, HZ and WM contributed to study conception and design. QS, JH, XW, JZ and KC recruited participants and conducted the study. YX and ZY conducted sample testing. JY revised the manuscript. All authors have read and agreed to the submitted version of the manuscript. Competing interests Weining Meng and Qianqian Xin are current employee of Sinovac Life Sciences Co., Ltd. Yanqing Zhao, Hengming Zhang, and Jianxing Yu are current employees of Sinovac Biotech Co., Ltd. Both companies are subsidiaries of Sinovac holdings. The other authors declare no competing interests. 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Nat Immunol. 23, (2022). Krammer F, Srivastava K, Alshammary H, Amoako AA, Awawda MH, Beach KF, Bermúdez-González MC, Bielak DA, Carreño JM, Chernet RL, Eaker LQ, Ferreri ED, Floda DL, Gleason CR, Hamburger JZ, Jiang K, Kleiner G, Jurczyszak D, Matthews JC, Mendez WA, Nabeel I, Mulder LCF, Raskin AJ, Russo KT, Salimbangon AT, Saksena M, Shin AS, Singh G, Sominsky LA, Stadlbauer D, Wajnberg A, Simon V. Antibodies Responses in Seropositive Persons after a Single Dose of SARS-CoV-2 mRNA Vaccine. N Engl J Med. 384, (2021). Fraley E, LeMaster C, Geanes E, Banerjee D, Khanal S, Grundberg E, Selvarangan R, Bradley T. Humoral immune responses during SARS-CoV-2 mRNA vaccine administration in seropositive and seronegative individuals. BMC Med. 19, (2021). Guidelines for grading standards of adverse events in clinical trials of preventive vaccines. China National Medical Products Administration. https://www.nmpa.gov.cn/xxgk/ggtg/qtggtg/20191231111901460.html (2023). Li YP, Liang ZL, Gao Q, et al. Safety and immunogenicity of a novel human enterovirus 71 (EV71) vaccine: a randomized, placebo-controlled, double-blind, phase I clinical trial. Vaccine 30, (2012). Jochum S, Kirste I, Hortsch S, Grunert VP, Legault H, Eichenlaub U, Kashlan B, Pajon R. Clinical Utility of Elecsys Anti-SARS-CoV-2 S Assay in COVID-19 Vaccination: An Exploratory Analysis of the mRNA-1273 Phase 1 Trial. Front Immunol. 12, (2022). Additional Declarations Yes there is potential Competing Interest. Weining Meng and Qianqian Xin are current employee of Sinovac Life Sciences Co., Ltd. Yanqing Zhao, Hengming Zhang, and Jianxing Yu are current employees of Sinovac Biotech Co., Ltd. Both companies are subsidiaries of Sinovac holdings. The other authors declare no competing interests. Supplementary Files Supplementary202308.docx Supplementary Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3251584","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":232739031,"identity":"f4eb3a9d-ae30-4a49-80bd-8f242ab2cdf5","order_by":0,"name":"Weining Meng","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAv0lEQVRIiWNgGAWjYPACGwY2UrWkka7lMAlqddt7D7/m3XHenk+6+ZjEjxoGeX6xA/i1mJ05l2bNe+Z2YpvMsTTJnmMMhjNnJxDQciPHzDi37XYCm0SOsQFvA0OCwW1CWu6/AWk5Zw/SYviXKC03eIwf57YdYGyTyDF8TJwtZ3LMmP+2JSe2SaQlPpY5JkGEX46fMf44s83OXn5G8oGDb2ps5PmlCWgBAjYJJI4ETmXIgPkDUcpGwSgYBaNg5AIA5fQ/me5rX8UAAAAASUVORK5CYII=","orcid":"","institution":"Sinovac Life Sciences Co., Ltd.","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Weining","middleName":"","lastName":"Meng","suffix":""},{"id":232739032,"identity":"25564596-1e0a-45bd-b336-8a1deda11911","order_by":1,"name":"Qin Sun","email":"","orcid":"","institution":"Jiangsu Provincial Center for Disease Control and Prevention","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Qin","middleName":"","lastName":"Sun","suffix":""},{"id":232739033,"identity":"e639ee01-31ab-4b03-b31b-6d79947e6c55","order_by":2,"name":"Ying Xie","email":"","orcid":"","institution":"Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College/National Institutes for Food and Drug Control","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ying","middleName":"","lastName":"Xie","suffix":""},{"id":232739034,"identity":"f81137c3-4927-464e-bdad-8e27b143ced1","order_by":3,"name":"Yanqing Zhao","email":"","orcid":"","institution":"Sinovac Biotech Co., Ltd.","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yanqing","middleName":"","lastName":"Zhao","suffix":""},{"id":232739035,"identity":"6d9eeade-e35f-473f-8633-3ef3359d3834","order_by":4,"name":"Jialei Hu","email":"","orcid":"","institution":"Jiangsu Provincial Center for Disease Control and Prevention","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jialei","middleName":"","lastName":"Hu","suffix":""},{"id":232739036,"identity":"b2c58cc6-56bd-4b7a-a1cf-79fa23612db6","order_by":5,"name":"Xianghong Wu","email":"","orcid":"","institution":"Sheyang County Center for Disease Control and Prevention","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xianghong","middleName":"","lastName":"Wu","suffix":""},{"id":232739037,"identity":"85c4db0b-0e64-4638-82be-bb73dbbe6729","order_by":6,"name":"Jing Zhang","email":"","orcid":"","institution":"Sheyang County Center for Disease Control and Prevention","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jing","middleName":"","lastName":"Zhang","suffix":""},{"id":232739038,"identity":"ffa87d55-94f0-4660-b106-3512c8087f95","order_by":7,"name":"Qianqian Xin","email":"","orcid":"","institution":"Sinovac Biotech","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Qianqian","middleName":"","lastName":"Xin","suffix":""},{"id":232739039,"identity":"56772e9a-e2b1-453e-888e-7989e37d55c5","order_by":8,"name":"Jianxing Yu","email":"","orcid":"","institution":"Sinovac Biotech Co., Ltd.","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jianxing","middleName":"","lastName":"Yu","suffix":""},{"id":232739040,"identity":"1159e038-94ea-45f5-8a5e-b06a807b3512","order_by":9,"name":"Hengming Zhang","email":"","orcid":"","institution":"Sinovac Biotech Ltd.","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hengming","middleName":"","lastName":"Zhang","suffix":""},{"id":232739041,"identity":"167d520f-e193-40e0-aa3c-b572dedcaa34","order_by":10,"name":"Zhifang Ying","email":"","orcid":"","institution":"National Institutes for Food and Drug Control","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhifang","middleName":"","lastName":"Ying","suffix":""},{"id":232739042,"identity":"2144fa35-b79e-4fc9-bd62-51738f5a52bc","order_by":11,"name":"Kai Chu","email":"","orcid":"","institution":"Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu Province, China","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kai","middleName":"","lastName":"Chu","suffix":""}],"badges":[],"createdAt":"2023-08-10 09:16:54","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3251584/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3251584/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":43143319,"identity":"a8241a45-32a2-4f7e-8ee2-94f524a40ee0","added_by":"auto","created_at":"2023-09-14 16:25:09","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":126316,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStudy profile\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3251584/v1/01d03d098f9eb6df8573044b.jpeg"},{"id":43143318,"identity":"face3ff1-8773-4970-95d8-a413e5fb2000","added_by":"auto","created_at":"2023-09-14 16:25:09","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":14407,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eNeutralizing antibodies levels against prototype strain and variants 28 days and 6 months post full immunization in Chinese children, by age (3-5 years, 6-11 years)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-3251584/v1/6aeb77f0e86be5feeab3d9bc.png"},{"id":47780908,"identity":"e81e4dc6-f610-4de8-8451-a64e29f4577a","added_by":"auto","created_at":"2023-12-07 11:28:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":530860,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3251584/v1/1874d68c-a5cc-4e01-96a5-f6aaf0cdb565.pdf"},{"id":43143321,"identity":"22a9aec8-bc95-48b5-b9b1-772df4f22f57","added_by":"auto","created_at":"2023-09-14 16:25:09","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":33088,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary\u003c/p\u003e","description":"","filename":"Supplementary202308.docx","url":"https://assets-eu.researchsquare.com/files/rs-3251584/v1/026927260e34f43f0d797823.docx"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nWeining Meng and Qianqian Xin are current employee of Sinovac Life Sciences Co., Ltd. Yanqing Zhao, Hengming Zhang, and Jianxing Yu are current employees of Sinovac Biotech Co., Ltd. Both companies are subsidiaries of Sinovac holdings. The other authors declare no competing interests.","formattedTitle":"Immunogenicity and safety of CoronaVac in children in an immuno-bridging phase 3 clinical trial","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCoronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has been spreading around the world\u003csup\u003e1\u003c/sup\u003e, resulting in large morbidity and mortality to people of all ages. Although most children experienced the illness with less severity and fewer deaths were reported compared to adults, critical cases such as multisystem inflammatory syndrome in children (MIS-C) kept appearing despite the low incidence, especially in children with underlying medical conditions\u003csup\u003e2,3,4\u003c/sup\u003e. Children play an important role in the transmission of the disease in communities or households\u003csup\u003e5,6\u003c/sup\u003e. Thus, effective vaccination could not only protect children from severe complications, but also help to achieve herd immunity in all age groups\u003csup\u003e7,8\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCoronaVac is an inactivated SARS-CoV-2 vaccine developed by Sinovac Life Sciences (Beijing, China). Three phase 1/2 clinical trials have already shown that CoronaVac has good safety, tolerability and immunogenicity in children, adults and older people\u003csup\u003e9,10,11\u003c/sup\u003e. A phase 3 clinical trial in Brazilian adults showed favorable efficacy of CoronaVac in preventing COVID-19 after 2 doses of vaccination\u003csup\u003e12\u003c/sup\u003e. On February 5, 2021, CoronaVac was approved for conditional marketing in China by the National Medical Products Administration (NMPA) (approval number: 2021S00156, 2021S00157). It was recommended for use in people aged 3 years and above and was one of the most widely used COVID-19 vaccine in China. CoronaVac was also listed for emergency use by World Health Organization (WHO) in people aged 18 years and above on June 1, 2021, and was extended to children aged 3\u0026ndash;17 years on November 2, 2022\u003csup\u003e13\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e Although multiple studies on the protective efficacy of CoronaVac have been obtained abroad, the protective effect in Chinese children is still lacking in the evaluation. Due to strict epidemic control measures in 2021, there were only a few cases of COVID-19 in China, and it was impossible to conduct large-scale efficacy studies. No surrogate endpoint of COVID-19 vaccine has been established; however, previous studies had demonstrated that vaccine efficacy might be positively correlated to neutralizing antibodies levels\u003csup\u003e14,15\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTo further provide immunogenicity and safety data of CoronaVac in Chinese children, this phase 3 immuno-bridging clinical trial was initiated in November 2021. The objectives of this study were to assess the superior immunogenicity of CoronaVac in Chinese children aged 3\u0026ndash;11 years compared to Brazilian adults aged 18\u0026ndash;26 years, and the immunogenicity non-inferiority in Chinese children compared to overseas children. The cross-neutralization effect would also be evaluated considering the prevalence of the SARS-CoV-2 variants.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n\u003ch2\u003eBaseline Demographics\u003c/h2\u003e\n\u003cp\u003eIn November 2021, 1014 children were screened and 1000 were enrolled, including 502 aged 3\u0026ndash;5 years and 498 aged 6\u0026ndash;11 years. All the participants received the first dose vaccination and were included in the Full analysis set (FAS) and Safety set (SS)/Safety set of first dose (SS1). 983 participants completed the second dose vaccination, 867 of whom were included in the PPS for immunogenicity evaluation. In the control group, 327 Brazilian adults and 145 overseas children with serum samples pre- and post-immunization were included in PPS. The age of the Chinese children and overseas children were all of 3\u0026ndash;11 years, and the mean age of the Brazilian adults was 24.98 years old. In the PPS, no Chinese children and overseas children were seropositive pre-vaccination, and 296 (90.52%) Brazilian adults were seronegative pre-vaccination (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e \u0026amp; Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eBaseline characteristics of study participants (PPS)\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eChinese children\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eBrazilian adults\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eOverseas children\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNo. of participants\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e867\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e327\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e145\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMale sex, no. (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e432(49.83)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e84(25.69)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e72(49.66)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMean Age in years, (interquartile range)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.67(2.22)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24.98(1.51)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.55(4.70)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u0026ndash;5 years, no. (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e404(46.60)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e52(35.86)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6\u0026ndash;11 years, no. (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e463(53.40)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e93(64.14)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSeronegative at baseline, no. (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e867(100.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e296(90.52)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e145(100.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n\u003ch2\u003eImmunogenicity in the Chinese children\u003c/h2\u003e\n\u003cp\u003eAt 28 days after the second dose, the GMT of neutralizing antibodies in Chinese children aged 3\u0026ndash;5 years and 6\u0026ndash;11 years were 220.60 and 180.98, and the GMC of anti-SARS-CoV-2 S antibodies were 1211.66 and 821.26, respectively (Supplementary Table\u0026nbsp;1).\u003c/p\u003e\n\u003cp\u003eFor baseline seronegative participants, the GMT of neutralizing antibodies at 28 days after the second dose in the Chinese children, Brazilian adults and overseas children were 198.47 (95%CI 189.44-207.93), 62.52 (95%CI 54.99\u0026ndash;71.08) and 202.58 (95%CI 166.29\u0026ndash;246.80), respectively. The seroconversion rates in the Chinese children, Brazilian adults and overseas children were 100% (95%CI 99.58\u0026ndash;100.00), 97.64% (95%CI 95.19\u0026ndash;99.04), and 100% (95%CI 97.49\u0026ndash;100.00), respectively. All the Chinese children turned seropositive at 28 days after the second dose. According to the covariance model analysis, the GMT of neutralizing antibodies in the Chinese children was superior to that of the Brazilian adults, with an adjusted GMT ratio of 3.18 (95%CI 2.85\u0026ndash;3.54); while the GMT of neutralizing antibodies in the Chinese children was non-inferior to that of the overseas children, with an adjusted GMT ratio of 0.98 (95%CI 0.85\u0026ndash;1.13) (P\u0026thinsp;=\u0026thinsp;0.7727). The seroconversion rate was also insignificant between the Chinese children and overseas children, with a rate difference of 0.00% (95%CI -0.44-2.58) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e \u0026amp; Supplementary Table\u0026nbsp;2 and Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eImmunogenicity analysis between Chinese children and Brazilian adults/overseas children in the seronegative participants at baseline (PPS)\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eChinese children\u003c/p\u003e\n\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;867)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eBrazilian adults\u003c/p\u003e\n\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;296)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eOverseas children\u003c/p\u003e\n\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;145)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ePre-vaccination\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGMT (95%CI)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.03\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.03\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e2.03\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e28 days after the second dose #\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGMT (95%CI)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e198.47 (189.44,207.93)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e62.52 (54.99,71.08)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e202.58 (166.29,246.80)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAdjusted GMT\u003csup\u003e1\u003c/sup\u003e, (95%CI)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e198.48 (187.84, 209.72)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e62.5 (56.89, 68.69)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e202.57 (178.08, 230.44)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAdjusted GMT ratio\u003csup\u003e2\u003c/sup\u003e, (95%CI)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.18 (2.85, 3.54)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e0.98 (0.85, 1.13)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSeroconversion rate, %, (95%CI)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e100 (99.58, 100.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e97.64 (95.19, 99.04)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e100 (97.49, 100.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRate difference\u003csup\u003e3\u003c/sup\u003e, %, (95%CI)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e0.00 (-0.44, 2.58)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\"\u003eAbbreviations: GMT, geometric mean titer; 95%CI, 95% confidence interval; Seroconversion was defined as a titer of neutralizing antibodies\u0026thinsp;\u0026ge;\u0026thinsp;1:8 post-vaccination in subjects with seronegative neutralizing antibodies pre-vaccination.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\"\u003e\u003csup\u003e#\u003c/sup\u003e For Brazilian adults, the serum samples were collected at 14 days after the second dose.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\"\u003e\u003csup\u003e1\u003c/sup\u003e Calculated by covariance analysis model, adjusting for pre-vaccination neutralizing antibody titers.\u003cbr /\u003e \u003csup\u003e2\u003c/sup\u003e Ratio values presented were those of Chinese children versus Brazilian adults, or Chinese children versus overseas children.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\"\u003e\u003csup\u003e3\u003c/sup\u003e Rate differences presented was of Chinese children versus overseas children.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n\u003cp\u003eAt 6 months after the second dose, the GMT of neutralizing antibodies in children aged 3\u0026ndash;5 years and 6\u0026ndash;11 years were 19.73 and 9.22, respectively, and the seropositive rates were 94.87% and 64.64%, respectively (Supplementary Table\u0026nbsp;1).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n\u003ch2\u003eCross-neutralization against other SARS-CoV-2 variants in Chinese children\u003c/h2\u003e\n\u003cp\u003eBefore immunization, neutralizing antibodies of all the participants were negative against the variant strains. At 28 days after the second dose, the seropositive rates of neutralizing antibodies in the 3\u0026ndash;5 years group against Gamma, Delta and Omicron strains were 99.33%, 97.33% and 17.33%, respectively, and in the 6\u0026ndash;11 years group were 99.33%, 96.00% and 8.67%, respectively. At 6 months after the second dose, the seropositive rates dropped significantly, with the neutralizing antibodies in the 3\u0026ndash;5 years group against Gamma, Delta and Omicron strains were 73.44%, 40.63% and 2.68%, respectively, and in the 6\u0026ndash;11 years group were 30.33%, 23.01% and 0.21%, respectively. The neutralizing antibodies level of the Omicron strain at every timepoint post-vaccination was significantly lower than those of the prototype strain and other two variants (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n\u003ch2\u003eSafety\u003c/h2\u003e\n\u003cp\u003eSafety analysis was conducted in SS subset. The incidences of overall ARs were generally similar among the two groups- 42.83% in the 3\u0026ndash;5 years group and 35.14% in the 6\u0026ndash;11 years group, respectively. Most of the ARs occurred within 7 days post-vaccination and were mild and moderate. Grade 3 adverse reactions were fever (1.90%) and cough (0.30%). Two most common systemic adverse reactions were cough (16.33% in the 3\u0026ndash;5 years group and 13.45% in the 6\u0026ndash;11 years group) and fever (11.95% in the 3\u0026ndash;5 years group and 12.65% in the 6\u0026ndash;11 years group). The most frequently reported local adverse reaction was injection-site pain (16.14% in the 3\u0026ndash;5 years group and 13.05% in the 6\u0026ndash;11 years group). From day 0 to six months after the second dose, 31 SAEs were reported by 13 participants. All the SAEs were deemed unrelated to the vaccine. (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eAdverse reactions from day 0 to 28 days after the second dose in Chinese children\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e3\u0026ndash;5 years (N\u0026thinsp;=\u0026thinsp;502)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e6\u0026ndash;11 years (N\u0026thinsp;=\u0026thinsp;498)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTotal (N\u0026thinsp;=\u0026thinsp;1000)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e215(42.83)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e175(35.14)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e390(39.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLocal reaction (injection site)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e148(29.48)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e131(26.31)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e279(27.90)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePain\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e81(16.14)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e65(13.05)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e146(14.60)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePruritus\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e15(2.99)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e9(1.81)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e24(2.40)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInduration\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e9(1.79)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e10(2.01)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e19(1.90)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSwelling\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e8(1.59)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e4(0.80)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e12(1.20)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRedness\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e4(0.80)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e5(1.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e9(0.90)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eSystemic reaction\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e98(19.52)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e78(15.66)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e176(17.60)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCough\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e82(16.33)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e67(13.45)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e149(14.90)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFever\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e60(11.95)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e63(12.65)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e123(12.30)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eVomiting\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e23(4.58)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e11(2.21)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e34(3.40)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRhinorrhea\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e20(3.98)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e12(2.41)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e32(3.20)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHeadache\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e5(1.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e18(3.61)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e23(2.30)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFatigue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e7(1.39)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e14(2.81)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e21(2.10)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDecreased appetite\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e9(1.79)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e10(2.01)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e19(1.90)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNausea\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e6(1.20)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e10(2.01)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e16(1.60)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDiarrhea\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e8(1.59)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e7(1.41)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e15(1.50)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAllergic reaction\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e2(0.40)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e2(0.40)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\"\u003e\n\u003cp\u003e4(0.40)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis was the first study to evaluate the immunogenicity of CoronaVac in children compared with that in adults. The immunogenicity results showed that the ratio of adjusted GMTs (95% CI) between the Chinese children aged 3\u0026ndash;11 years and the Brazilian adults aged 18\u0026ndash;26 years was 3.18, the lower limit of 95%CI was 2.85, which was higher than the superiority cut-off value of 3/2. Thus, the superior immunogenicity was claimed. According to the results of phase 3 clinical trial in adults in Brazil, the efficacy of CoronaVac against symptomatic COVID-19 was 50.7% and against severe symptoms was 100%. It is suggested in this study that the efficacy of CoronaVac in children population was favorable.\u003c/p\u003e \u003cp\u003eThrough the non-inferiority comparation, it was found that Chinese children and overseas children at the same age could produce similar levels of neutralizing antibodies after vaccination. The overseas children in the multi-center phase III clinical trial were from countries of South Africa, Chile, Malaysia and the Philippines, who were with different ethnicities. The results could indicate that CoronaVac has good immunogenicity cross different ethnic groups.\u003c/p\u003e \u003cp\u003eStratified by age, both neutralizing antibodies and anti-SARS-CoV-2 S antibodies levels increased with decreasing age (Supplementary Table\u0026nbsp;1), which is consistent with the results from a previous children and adolescents study of CoronaVac\u003csup\u003e11\u003c/sup\u003e. These results further support that SARS-CoV-2 infections may result in less severe symptoms among children and adolescents compared to adults\u003csup\u003e16\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe superiority evaluation of neutralizing antibodies was conducted at different timepoints due to different vaccination schedules in the two groups\u0026mdash;day 0, 28 immunization schedule for Chinese children and day 0, 14 schedule for Brazilian adults. The superiority results also suggest that the day 0, 28 vaccination schedule might achieve better immune protection\u003csup\u003e17,18\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn baseline seropositive Brazilian adults, CoronaVac induced higher neutralizing antibodies levels compared to baseline seronegative ones (find the results in the supplementary). A similar phenomenon had also been found in the SARS-CoV-2 mRNA vaccine: a rapid immune response could be elicited by a single dose of mRNA vaccine in seropositive participants; their post-vaccination antibody titers were similar or above those of seronegative participants who received two doses of vaccination\u003csup\u003e19,20\u003c/sup\u003e. However, further research is needed to investigate if this stronger immune response could be elicited in children, which can help to develop better vaccination strategies.\u003c/p\u003e \u003cp\u003eLong-term immunogenicity at 6 months after the second dose declined significantly: the neutralizing antibody GMTs (prototype strain) decreased from 220.60 to 19.73 in the 3\u0026ndash;5 years group and from 180.98 to 9.22 in the 6\u0026ndash;11 years group. Similar declines were also present against the variant strains. What\u0026rsquo;s more, the cross-neutralization results indicated a weak immune response against the Omicron strain with two doses of CoronaVac, which suggested the necessity of booster vaccination.\u003c/p\u003e \u003cp\u003eThe safety data showed that CoronaVac was well tolerated in children aged 3\u0026ndash;11 years. The safety results in this study were comparable with the results in the Phase 1/2 pediatric clinical study in the same age group\u003csup\u003e11\u003c/sup\u003e. Most adverse reactions resolved in a few days with mild and moderate symptoms, and none of the SAE was deemed related to the vaccine.\u003c/p\u003e"},{"header":"Method","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n\u003ch2\u003eStudy design and participants\u003c/h2\u003e\n\u003cp\u003eThe study was a single-center, open-label and immuno-bridging clinical trial to evaluate the immunogenicity and safety of CoronaVac in Sheyang county, Jiangsu province, China. A total of 1000 participants were planned to be enrolled, including 500 children aged 3\u0026ndash;5 years and 500 children aged 6\u0026ndash;11 years. Main exclusion criteria included history of confirmed infection of SARS-CoV-2, contact history with someone infected with SARS-CoV-2 within 14 days prior to study entry, vaccination history of COVID-19 vaccine, and allergy to any vaccine component (for full inclusion and exclusion criteria, see the supplementary). Informed consents need to be signed by the guardians, and children aged 8 years and above should also provide written assents before enrollment. The study protocol and informed consent form were approved by the ethics committee of Jiangsu Center for Disease Control and Prevention (CDC). This trial was conducted in compliance with the Declaration of Helsinki, Good Clinical Practice, and Chinese regulatory requirements. The study was registered with ClinicalTrials.gov (NCT05137418).\u003c/p\u003e\n\u003cp\u003eTo conduct the immunogenicity superiority evaluation, the back-up serum samples of the phase III clinical trial in Brazil (clinical trial.gov NCT04456595), which were paired of pre- and post-immunization with sufficient volume for testing, were selected in order of numbering. The study was established in 2020 and designed as randomized, double-blind to evaluate the efficacy of CoronaVac with the vaccination schedule of 0,14 days in Brazilian adults aged 18\u0026ndash;59 years.\u003csup\u003e12\u003c/sup\u003e The serum samples were collected at 14 days after the second dose.\u003c/p\u003e\n\u003cp\u003eFor the non-inferiority evaluation, serum samples from overseas children in the multi-center phase III clinical trial (clinical trial.gov NCT04992260) were used. The serum samples were also paired of pre- and post-immunization with sufficient volume for testing, and selected in order of numbering. The study was conducted in children and adolescents from Chile, South Africa, Malaysia and the Philippines in 2021, for assessing the efficacy of CoronaVac in children aged 6 months to 17 years old. The overseas children received 2 does of CoronaVac in 28 days apart and collected the serum samples at 28 days after the second dose.\u003c/p\u003e\n\u003cp\u003eIn order to control the bias in vaccine immunogenicity caused by the large age span, the serum samples of Brazilian adults aged 18\u0026ndash;26 years were used for superiority evaluation, and the samples of overseas children aged 3\u0026ndash;11 years were used for non-inferiority evaluation.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n\u003ch2\u003eStudy vaccine\u003c/h2\u003e\n\u003cp\u003eCoronaVac was an inactivated SARS-CoV-2 vaccine and was created from African green monkey kidney cells (Vero cells), which had been inoculated with SARS-CoV-2 ancestral strain (CZ02). The SARS-CoV-2 strain was then harvested, inactivated, concentrated, purified, and adsorbed onto aluminum hydroxide. The vaccine was prepared in a Good Manufacturing Practice-accredited facility of Sinovac, which was periodically inspected by the NMPA committee for compliance. CoronaVac was packaged in a pre-filled syringe with 600 SU (3\u0026micro;g) of SARS-CoV-2 antigen per dose (0.5 mL/syringe).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n\u003ch2\u003eParticipants assignment\u003c/h2\u003e\n\u003cp\u003eParticipants were assigned into two groups according to the age of 3\u0026ndash;5 years or 6\u0026ndash;11 years. Every participant was assigned an open-label vaccine number in chronological order in each group and received the vaccine with the same number.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n\u003ch2\u003eStudy procedure\u003c/h2\u003e\n\u003cp\u003eAfter the informed consent forms signed and dated by participants and/or their guardians, and physical examination and inclusion and exclusion criteria screening were passed, participants would be enrolled into the study. Participants received 2 doses of CoronaVac intramuscularly in the deltoid region with an interval of 28 days. About 3.5ml venous blood were collected from all participants pre-vaccination, 28 days and 6 months post second-dose vaccination, respectively. The immunologic assays of the neutralizing antibodies of all the serum samples were conducted by China National Institutes for Food and Drug Control (CNIFDC).\u003c/p\u003e\n\u003cp\u003eAfter each vaccination, participants were observed for 30 minutes for immediate adverse reactions (ARs, adverse events with reasonable causal relationship with study vaccine). Solicited local adverse events (AEs) (e.g., injection-site pain, induration, swelling) and systemic AEs (e.g., allergic reaction, fever, headache, cough) within 7 days after each dose were required to be recorded on the diary cards by participants or their guardians. Unsolicited AEs occurring within 28 days after each dose were also collected by spontaneous report from the participants combined with the regular visit (which occurred on day 8 and day 28 after each dose). Serious adverse events (SAE) were monitored until 12 months after the second dose and followed-up until resolution if any. The severity of AE was graded according to the China National Medical Products Administration guidelines\u003csup\u003e21\u003c/sup\u003e. The causal association between adverse events and vaccination was determined by site investigators.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n\u003ch2\u003eImmunogenicity assessment\u003c/h2\u003e\n\u003cp\u003eThe neutralizing antibodies titers against live SARS-CoV-2 (prototype strain CZ01, Gamma strain P.1, Delta strain B.1.167.2, Omicron strain BA.1) were quantified by the micro-cytopathogenic effect assay\u003csup\u003e22\u003c/sup\u003e. The primary immunogenicity endpoint was the geometric mean titer (GMT) of neutralizing antibodies against prototype strain on day 28 after the second dose. Secondary immunogenicity endpoints were seropositivity rate (defined as neutralizing antibodies\u0026thinsp;\u0026ge;\u0026thinsp;1:8) and seroconversion rate of neutralizing antibodies at 28 days and 6 months after the second dose, and the GMT of neutralizing antibodies at 6 months after full vaccination. Seroconversion was defined as (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e) neutralizing antibodies titers\u0026thinsp;\u0026ge;\u0026thinsp;1:8 post-vaccination in subjects with seronegative neutralizing antibodies pre-vaccination or (\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e) neutralizing antibodies titers increased by 4 times or more post-vaccination in subjects who were seropositive pre-vaccination. The superiority would be claimed if the lower limit of the 95% confidence interval (95% CI) of the adjusted GMT ratio was \u0026gt;\u0026thinsp;3/2 after adjusting for pre-vaccination neutralizing antibody titers. The non-inferiority would be claimed if (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e) the lower limit of the 95% CI of the adjusted GMT ratio was \u0026gt;\u0026thinsp;2/3 and (\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e) the lower limit of the 95% CI of the seroconversion rate difference was \u0026gt;-5%.\u003c/p\u003e\n\u003cp\u003eMeanwhile, the antibody levels against the Receptor Binding Domain (RBD) of the S protein of the Chinese children at 28 days after the second dose were quantified by using the Roche Anti-SARS-CoV-2 S assay\u003csup\u003e23\u003c/sup\u003e, with the corresponding endpoints of seroconversion rate and geometric mean concentration (GMC).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n\u003ch2\u003eSafety assessment\u003c/h2\u003e\n\u003cp\u003eSafety assessment was performed throughout the study. Safety endpoints included ARs within 0\u0026ndash;28 days after each dose vaccination, and SAEs following the first dose inoculation to 12 months after the second dose vaccination.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n\u003ch2\u003eStatistical analysis\u003c/h2\u003e\n\u003cp\u003eThe sample size was determined based on the superiority and non-inferiority design. To achieve 90% power at a two-sided 5% significance level, with logarithmic standard deviation 0.7 (based on previous research results), and assumed the sample size of Brazilian adults was at least 260, we calculated that the sample size was 462 for Chinese children in the superiority design. While in the non-inferiority design comparing serum of overseas children, the sample size of each Chinese and overseas children group was calculated to be 333; meantime, assumed that the seroconversion rate of neutralizing antibodies post-immunization was 90%, the sample size of each group was calculated to be 775. To meet the maximum sample size requirement and a 20% drop-out rate, a total of 1000 Chinese children were included in this trial.\u003c/p\u003e\n\u003cp\u003eGMTs and corresponding 95% CIs were calculated on the basis of standard normal distribution of the log-transformed neutralizing antibodies titer. The adjusted GMTs were calculated by using the covariance analysis model, which took the mean of the log transformed neutralizing antibodies titer after immunization as the dependent variable, the logarithmic GMT before immunization as the covariate, and the group as the fixed effect. Calculate the least squares mean of adjusted GMT ratio (adjusted GMT of Chinese children/ Brazilian adults or overseas children) and corresponding 95%CI for superiority comparison. The 95% CI of seroconversion rate difference were estimated using the Miettnen-Nurminen method.\u003c/p\u003e\n\u003cp\u003eThe immunogenicity endpoints were evaluated in the per protocol set (PPS) which included participants who had received 2 doses of CoronaVac and had available antibodies results pre- and post-vaccination. The superiority and non-inferiority evaluation were in the PPS of the participants who were seronegative at baseline. The safety endpoints were evaluated in the safety set (SS) which included participants who received at least 1 dose of CoronaVac. SAS (version 9.4) was used for statistical analysis.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe studies involving human participants were reviewed and approved by ethics committee of Jiangsu Provincial CDC (approval number: JSJK2021-A036-01). The participants and/or their legal guardian provided written informed consent to participate in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to express their thanks to the staff of Jiangsu Provincial CDC and to the local CDCs (Sheyang Center for Disease Control and Prevention) for their efforts in leading the field work for this trial. We would like to express our sincere gratitude to all participants in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eQS, YX and YZ participated in manuscript drafting. YZ, KC, QX, JH, HZ and WM contributed to study conception and design. QS, JH, XW, JZ and KC recruited participants and conducted the study. YX and ZY conducted sample testing. JY revised the manuscript. All authors have read and agreed to the submitted version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWeining Meng and Qianqian Xin are current employee of Sinovac Life Sciences Co., Ltd. Yanqing Zhao, Hengming Zhang, and Jianxing Yu are current employees of Sinovac Biotech Co., Ltd. Both companies are subsidiaries of Sinovac holdings. The other authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWorld Health Organization. Coronavirus Disease (COVID-19) Dashboard. https://covid19.who.int/ (2023).\u003c/li\u003e\n\u003cli\u003ePatel JM. Multisystem Inflammatory Syndrome in Children (MIS-C). \u003cem\u003eCurr Allergy Asthma Rep\u003c/em\u003e. 22, (2022). \u003c/li\u003e\n\u003cli\u003eCui X, Zhao Z, Zhang T, Guo W, Guo W, Zheng J, Zhang J, Dong C, Na R, Zheng L, Li W, Liu Z, Ma J, Wang J, He S, Xu Y, Si P, Shen Y, Cai C. 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Should children be vaccinated against COVID-19? \u003cem\u003eArch Dis Child.\u003c/em\u003e 107, (2022). \u003c/li\u003e\n\u003cli\u003eZhang Y, Zeng G, Pan H, Li C, Hu Y, Chu K, Han W, Chen Z, Tang R, Yin W, Chen X, Hu Y, Liu X, Jiang C, Li J, Yang M, Song Y, Wang X, Gao Q, Zhu F. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. \u003cem\u003eLancet Infect Dis.\u003c/em\u003e 21, (2021).\u003c/li\u003e\n\u003cli\u003eWu Z, Hu Y, Xu M, Chen Z, Yang W, Jiang Z, Li M, Jin H, Cui G, Chen P, Wang L, Zhao G, Ding Y, Zhao Y, Yin W. 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Humoral immune responses during SARS-CoV-2 mRNA vaccine administration in seropositive and seronegative individuals. \u003cem\u003eBMC Med.\u003c/em\u003e 19, (2021). \u003c/li\u003e\n\u003cli\u003eGuidelines for grading standards of adverse events in clinical trials of preventive vaccines. China National Medical Products Administration. https://www.nmpa.gov.cn/xxgk/ggtg/qtggtg/20191231111901460.html (2023).\u003c/li\u003e\n\u003cli\u003eLi YP, Liang ZL, Gao Q, et al. Safety and immunogenicity of a novel human enterovirus 71 (EV71) vaccine: a randomized, placebo-controlled, double-blind, phase I clinical trial. \u003cem\u003eVaccine\u003c/em\u003e 30, (2012).\u003c/li\u003e\n\u003cli\u003eJochum S, Kirste I, Hortsch S, Grunert VP, Legault H, Eichenlaub U, Kashlan B, Pajon R. Clinical Utility of Elecsys Anti-SARS-CoV-2 S Assay in COVID-19 Vaccination: An Exploratory Analysis of the mRNA-1273 Phase 1 Trial. \u003cem\u003eFront Immunol.\u003c/em\u003e 12, (2022).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3251584/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3251584/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eSeveral clinical trials demonstrated that CoronaVac had favorable efficacy and immunogenicity in adults and children. This phase 3, open-label, immuno-bridging clinical trial assessed the superior immunogenicity of CoronaVac in Chinese children aged 3\u0026ndash;11 years compared to Brazilian adults aged 18\u0026ndash;26 years, and its non-inferiority in Chinese children compared to overseas children (NCT05137418). A sample size of 1000 healthy children aged 3\u0026ndash;11 years were enrolled in China. Two doses of CoronaVac were given 28 days apart. Superiority and non-inferiority analysis were conducted by assessing the neutralizing antibodies titers against SARS-CoV-2. The geometric mean titer (GMT) of neutralizing antibodies in Chinese children on day 28 post second dose vaccination was 198.47 (95%CI 189.44-207.93), superior to that of the Brazilian adults (62.52, 95%CI 54.99\u0026ndash;71.08) with the adjusted GMT ratio of 3.18 (95%CI 2.85\u0026ndash;3.54); and it was non-inferior compared to the overseas children (202.58, 95%CI 166.29\u0026ndash;246.80) with the adjusted GMT ratio of 0.98 (95%CI 0.85\u0026ndash;1.13) and seroconversion rate difference of 0.00% (95%CI -0.44-2.58). Most adverse reactions were mild and moderate. All of the serious adverse events (SAEs) were considered unrelated to vaccination. CoronaVac showed good immunogenicity and safety in children aged 3\u0026ndash;11 years. The results suggested that CoronaVac could have favorable protection against COVID-19 in children.\u003c/p\u003e","manuscriptTitle":"Immunogenicity and safety of CoronaVac in children in an immuno-bridging phase 3 clinical trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-09-14 16:25:04","doi":"10.21203/rs.3.rs-3251584/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f6ee8e99-cd2e-4582-b36a-2f185e0dcf16","owner":[],"postedDate":"September 14th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":24584799,"name":"Biological sciences/Immunology/Vaccines/Inactivated vaccines"},{"id":24584800,"name":"Biological sciences/Immunology"}],"tags":[],"updatedAt":"2023-12-07T11:20:11+00:00","versionOfRecord":[],"versionCreatedAt":"2023-09-14 16:25:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3251584","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3251584","identity":"rs-3251584","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}