Abstract
Objective
To evaluate the safety of primary immunization using CoronaVac® among population aged 3 years and above in a large-scale use.
Method
A multi-center open-label study was carried out in 11 provinces of China. Individuals aged 3 years and older who had no history of COVID-19 vaccination or had received only one dose of CoronaVac® were enrolled in this study. Adults and elderly with or without underlying medical conditions(UMCs) were also recruited. Eligible participants received one or two doses of CoronaVac® with an interval of 28 days. Demographic information, vaccination and the occurrence of adverse events were recorded by participants or guardians using data collection system designed for this study. All adverse events occurred within 6 months after the second dose of vaccination were collected. The incidence of adverse events that cannot be ruled out as being caused by the vaccine were calculated to assess the safety of CoronaVac®. This study is registered with ClinicalTrials. Gov (NCT04911790 and NCT04992208).
Results
A total of 162,691 participants have been included in this study and 89.50 % had finished primary immunization. Among adults and elderly, people with UMCs accounted for 25.85 %, with the top five disease being hypertension, diabetes, chronic gastritis, coronary heart disease(CHD) and kidney stone. The overall incidence of adverse reactions (ARs) within 6 months after the second vaccination was 2.70 %, with incidence for children and adolescents, adults, and elderly being 2.03 %, 3.46 %, and 1.90 %, respectively. Most ARs were mild (grade 1). Pain at the injection sites, fatigue, induration/swelling, and headache were the most common symptoms, occurring in 1.64 %, 0.46 %, 0.31 % and 0.24 %, respectively. No serious adverse events related to vaccines were reported. No adverse events of special interest (AESIs) were identified.
For children and adolescents, children aged 3–5 years had the highest incidence of ARs of 3.29 %.
The incidence of ARs among those aged 18 years and older with and without UMCs were 2.81 % and 2.99 %, respectively, with no statistical significance between two groups(P = 0.089). And people with coronary heart disease had higher AR incidence compared to those with other UMCs, but the most common symptoms was pain at the injection site.
Conclusion
CoronaVac® is safe in a large-scale use and shows well-tolerance for children and adolescents and people with underlying medical conditions. Further studies need to be conducted to explore the relation of ARs incidence to age or different kinds of UMCs.
1. Introduction
Coronavirus disease (COVID-19) is an infectious disease caused by the SARS-CoV-2 virus. Most people infected with the virus will experience mild to moderate respiratory illness and recover without requiring special treatment. However, some will become seriously ill and require medical attention, especially the elderly and those with underlying medical conditions like cardiovascular disease, diabetes, chronic respiratory disease, or cancer[1]. For now, the pandemic has not been fully controlled yet, and will continue to threaten the global public health. Since the outbreak of COVID-19 at the end of 2019, it has spread over 200 countries and regions around the world and brought much inconvenience to society and people’s daily life. As of 12 June 2022, over 533 million confirmed cases and over 6.3 million deaths have been reported globally[2].
COVID-19 vaccination is one of the most effective way to help control the pandemic. Various vaccines have been used to fight against the pandemic, and lots of evidence showed their effectiveness. Studies showed two doses of vaccination were 85 % effective at preventing SARSCoV-2 infections, 97 % for symptomatic COVID-19, 93 % for hospitalization, 96 % for Intensive Care Unit (ICU) admissions, and 95 % effective for COVID-19-related death, respectively[3]. And evidence had showed acceptable safety profiles of different COVID-19 vaccines; the pooled incidence of Adverse Events Following Immunization(AEFI) for inactivated vaccines, mRNA based vaccines and viral-vector vaccines were 23.0 %, 48 %, and 76 %[4]. Vaccines also maintained good and robust safety in children and adolescents[5] and in specific populations such as cancer patients, organ transplant recipients, patients with rheumatic and musculoskeletal diseases, pregnant women and the elderly[3], [6], [7], [8], [9], [10]. However, most evidence came from randomized clinical trials (RCTs) [4], [5], [3].
In China, at least five different COVID-19 vaccines have been conditionally approved for emergency use. CoronaVac® was conditionally approved for use among population aged more than 18 years in February 2021, with good safety, tolerability and immunogenicity in phase Ⅰ/Ⅱ [11], [12] as well as great efficacy in phase 3 clinical trials carried out in Chile and Turkey [13], [14]. With clinical evidence[15], CoronaVac was approved for emergency use among population aged 3 to 17 years old In July 2021 in China. The most common symptoms after vaccination were injection site pain, headache, fever and fatigue[11], [12], [13], [14], [15]. However, there was little evidence reporting about the safety of the inactivated SARS-CoV-2 vaccine in a large-scale use among people. Therefore, we conducted this study among people aged 3 years and above to explore the safety of CoronaVac®.
2. Method
2.1. Study design and participants
A multi-center open-label study aimed to assess the safety of inactivated SARS-CoV-2 vaccine (CoronaVac®) among adults aged 18 years and above was conducted in 11 provinces in China including Yunnan, Liaoning, Heilongjiang, Anhui, Fujian, Jiangxi, Hubei, Guangxi, Chongqing, Guizhou and Gansu. After the approval of CoronaVac® on emergency use among children and adolescents aged 3–17 years, 9 of 11 provinces agreed to include children and adolescents as participants in this study. A total of 23 sites in 11provinces was included in this study.
Each province was designated to recruit 11,000 adults aged 18 years and older as well as 3000 children and adolescents. There should be at least 4000 elderly aged 60 years and above and 2000 with underlying medical conditions included in adults and elderly.
The underlying medical conditions (UMC) should be diagnosed by health institutions of the county level or above. The list of UMC in this study included coronary heart disease(CHD), myocarditis, chronic heart failure, chronic pulmonary heart disease, atherosclerosis, rheumatic heart disease, hypertension, cerebral infarction, post-coronary stenting, chronic obstructive pulmonary disease(COPD), chronic bronchitis, obstructive emphysema, bronchial asthma, idiopathic pulmonary fibrosis, pulmonary heart disease, tuberculosis (inactive), chronic gastritis, chronic viral hepatitis, cirrhosis, chronic pancreatitis, chronic pyelonephritis, chronic glomerulonephritis, kidney stones, nephrotic syndrome, sickle cell disease, thalassemia, obesity, diabetes, hyperthyroidism, hypothyroidism, systemic lupus erythematosus, gout, rheumatoid arthritis, cancer, uterine fibroids, organ transplantation or hematopoietic stem cell transplantation and others.
This study was approved by the Ethics Committee of Yunnan Center for Disease Control and Prevention(YNCDC)(ref. number 2021–5). Written informed consent was obtained from each participant aged 18 years and older. For adolescents aged 8 to 17 years old, informed consent was obtained from both participants themselves and their guardians; for children aged 3 to 7 years old, informed consent was obtained from their guardians. All procedures were performed in accordance with the guidelines of institutional ethics committee and adhered to the tenets of the Declaration of Helsinki.
This study is registered with ClinicalTrials. Gov (NCT 04,911,790 and NCT04992208).
2.2. Procedures
Individuals aged 3 years and older with no history of COVID-19 vaccination or had received only one dose of CoronaVac® were screened for eligibility. Eligible participants who or whose guardians agreed to sign the written informed consent and report safety information after each dose of vaccination in the follow-up period were included in this study.
Exclusion criteria included: (1) individuals who have experienced severe allergic reactions to vaccines in the past (e.g. acute anaphylaxis, angoneurotic edema, dyspnea, etc.); (2) individuals with severe neurological diseases (e.g., transverse myelitis, Guillain-Barré syndrome, and demyelinating diseases, etc.); and (3) individuals who suffered from acute diseases, acute exacerbation of chronic diseases or severe chronic diseases.
Data collection system and related smartphone appliance (APP) and spreadsheets used for this study were developed by Beijing Shengyuan Jiaye Biotechnology Co., ltd. Participants or their guardians who can use smartphones may download APP called Fangzhoumianyi to provide information. For those who cannot use smartphones, investigators of this study may use spreadsheets by interview or phone calls to collect information. All information will be transformed into the data collections system (http://fzmy.jy-ht.com.cn/fzmy/#/login) where investigators logged in to review data and verify the relation of adverse events to vaccines.
Information collected in this study included the basic information, vaccination and safety information. Basic information referred to participants’ height, weight, and other related demographic information (including underlying medical conditions); vaccination information (date and site) was collected after each dose of vaccination; safety follow-up need to be reported and filled at designated time. Indicators to assess the safety of CoronaVac® included the incidences of local and systemic adverse events(AEs), severe adverse events (SAEs) and adverse events of special interest (AESIs). Immediate adverse events were observed on-site in 30 min after each dose of vaccination. Follow-up for safety were required within 0 ∼ 7 days and the 28th day after each vaccination, and 3, 6, 9 and 12 months after the last dose of vaccination. Any adverse events occurred besides designated time also need to be recorded. Local and systemic AEs were collected within 28 days after each dose of vaccination; unsolicited AEs, SAEs and AESIs were collected through the entire study period, which referred to 1 year after the second vaccination.
All reported adverse events were assessed and graded by investigators according to the Guidelines for Grading the Adverse Events in Clinical Trials of Vaccines for Prophylaxis, issued by China National Medical Products Administration in 2019 (https://www.nmpa.gov.cn/xxgk/ggtg/qtggtg/20191231111901460.html).
The causality between adverse events and vaccination was determined by the investigators. Any adverse event determined as possibly, probably, or definitely related to vaccination was defined as an adverse reaction.
Local AEs included pain, induration, swelling, redness, rash and pruritus in the injection site; while systemic AEs consisted of fever (axillary temperature), acute anaphylaxis, mucocutaneous abnormality, diarrhea, anorexia, nausea, vomiting, muscle pain, headache, cough, fatigue.
Severe adverse events (SAEs) include hospitalization, significant disability, life-threatening or death, or congenital anomaly/birth defect. Adverse events of special interest (AESIs) for adults includes Bell's palsy, sudden deafness/hearing loss, brachial plexus neuritis/multiple neuritis, Guillain-Barre syndrome (GBS), thrombocytopenic purpura, allergic purpura, thrombosis. AESIs for children and adolescents includes pregnancy within 4 weeks after vaccination, Bell's palsy, systemic convulsions, Guillain-Barre syndrome (GBS), acute disseminated encephalomyelitis (ADEM), thrombocytopenia, immune allergic reaction, vasculitis, Multisystem Inflammatory Syndrome in children (MIS-C) and other systemic serious adverse events.
Any SAEs or AESIs once reported would be investigated and followed up by investigators until the event ended. The causality between SAEs or AESIs and vaccination was evaluated and decided by expert group. For each SAE, at least five experts, who came from clinical medicine, epidemiology, and other related sectors, would participate in the evaluation and discussion and finally decided the causality between SAEs and vaccination. Experts would review the SAEs reports and investigation results, and then made decision in terms of the pathogenesis, diagnosis and other related factors.
2.3. Vaccine
CoronaVac® was a Vero cell–based inactivated alum-adjuvanted SARS-CoV-2 vaccine developed by Sinovac Life Sciences Co., ltd. (lots A202104019, A202105020, D202106027, A202105034, A202106035, and D202105018). Vaccines used in this study was packaged in a syringe containing 600 SU of SARS-CoV-2 (CZ02 strain) antigen in a total volume of 0.5 ml and delivered by intramuscular injection.
Participants eligible for inclusion with no history of COVID-19 vaccination will receive two doses of CoronaVac® with an interval of 28 days(window period, 14 to 56 days); and those who already received one dose of CoronaVac® will get another dose with a 28-day interval(window period, 14 to 56 days).
2.4. Outcomes
The primary outcome of the study was the incidence of adverse reactions within 0–7 days after each dose of vaccination in all participants; the secondary outcome was the incidence of adverse reactions within 0–28 days after each dose of vaccination among all participants; the exploratory endpoints were the incidence of Severe adverse events (SAEs) and Adverse events of special interest (AESIs).
2.5. Statistical analysis
In this interim report, adverse events occurred within six months after the second dose of vaccination were collected and analyzed. The safety analyses included all participants who received at least one dose of CoronaVac®. Descriptive statistical analysis was used for demographic characteristics and incidence of AEs, quantitative variables was used as mean and standard deviation, and incidences were expressed as counts and percentages. Comparison of incidences of AEs was conducted using Chi-square test or Fisher’s exact test. A P-value<0.05 was considered to represent a statistically significant difference among the test populations. All statistical analyses were conducted using Graph Pad Prism, version 9.4.
Comparison of incidences was conducted among different populations(children and adolescents aged 3–17 years, adults aged 18–59 years and elderly aged 60 years and above) according to occurrence time, severity and symptoms of ARs. For children and adolescents, further comparison of ARs incidence was carried out among different age groups(3–5 years, 6–11 years and 12–17 years). And for adults and elderly, analysis was performed to explore the difference of ARs incidence among participants with or without underlying medical conditions(UMCs). Besides, comparison was also performed to explore the incidences of ARs between healthy participants and participants with top 5 UMCs according to different age groups(18–59 years and elderly aged 60 years and above).
3. Result
3.1. Study participants
The study for adults and elderly started on June 10th, 2021 and the study among children and adolescents started on July 24th, 2021. All the sites had finished participants recruitment by January 2022. A total of 162,691 participants from 11 provinces have been included in this study, of whom 84,931 (52.20 %) were male.
The age of participants ranged from 3 years old to 100 years old. The proportions of children and adolescents (3–17 years old), adults (18–59 years old) and elderly (aged more than 60 years old) were 19.08 % (31,041/162,691), 49.54 % (80,604/162,691) and 31.38 % (51,046/162,691), respectively.
Among adults and elderly, people with underlying medical conditions(UMCs) accounted for 25.85 % (34,033/131,650), with the top five disease being hypertension, diabetes, chronic gastritis, coronary heart disease(CHD) and kidney stone. Most people with UMCs were elderly (57.31 %,19,505/34,033).
The baseline demographic characteristics of the participants recruited in our study were showed in Table 1 .
Table 1.
The demographic information of participants.
| Demographic Information | Children and adolescents aged 3–17 years (N = 31041) |
Adults aged 18–59 years (N = 80604) |
Adults aged 60 + years (N = 51046) |
Total (N = 162691) |
|---|---|---|---|---|
| Age | ||||
| Mean ± SD | 9.45 ± 3.73 | 40.09 ± 12.65 | 68.53 ± 6.01 | 43.17 ± 22.73 |
| Sex | ||||
| Male, n(%) | 16,335 (52.62) | 43,607 (54.10) | 24,989 (48.95) | 84,931 (52.20) |
| Female, n(%) | 14,706 (47.38) | 36,997 (45.90) | 26,057 (51.05) | 77,760 (47.80) |
| Ethnicity | ||||
| Ethnic Han, n(%) | 22239(71.73) | 67075(83.24) | 43946(86.09) | 133260(81.94) |
| Minority, n(%) | 8764(28.27) | 13503(16.76) | 7098(13.91) | 29365(18.06) |
| Height (cm) | ||||
| Mean ± SD | 138.23 ± 21.40 | 164.70 ± 8.14 | 160.56 ± 8.26 | 158.35 ± 15.50 |
| Weight (kg) | ||||
| Mean ± SD | 32.90 ± 11.80 | 63.43 ± 11.89 | 59.50 ± 10.37 | 56.37 ± 16.23 |
| BMI | ||||
| Male | 16.76 | 23.67 | 22.92 | 22.13 |
| Female | 16.97 | 22.88 | 23.1 | 21.84 |
| BMI, n(%) | ||||
| <15 | 9535(30.72) | 0(0.00) | 0(0.00) | 0(0.00) |
| 15–18.4 | 12974(41.8 %) | 5331(6.61) | 3617(7.09) | 21922(14.42) |
| 18.5–23.9 | 7144(23.01) | 43512(53.98) | 28623(56.07) | 79279(52.16) |
| 24–27.9 | 633(2.04 %) | 23636(29.32) | 15036(29.46) | 39305(25.86) |
| ≥28 | 560(1.80) | 7553(9.37) | 3374(6.61) | 11487(7.56) |
| Underlying Medical Condition | ||||
| Yes, n(%) | N.A. | 14,528 (18.02) | 19,505 (38.21) | 34,033 (25.85) |
| Hypertension | N.A. | 5248(36.12) | 10823(55.49) | 16071(47.22) |
| Diabetes | N.A. | 1915(13.18) | 3423(17.55) | 5338(15.68) |
| Chronic Gastritis(CG) | N.A. | 2072(14.26) | 1517(7.78) | 3589(10.55) |
| Coronary heart disease(CHD) | N.A. | 479(3.3) | 1789(9.17) | 2268(6.66) |
| Kidney stone | N.A. | 1514(10.42) | 573(2.94) | 2087(6.13) |
| Cerebral infarction | N.A. | 456(3.14) | 1466(7.52) | 1922(5.65) |
| Chronic bronchiti | N.A. | 519(3.57) | 751(3.85) | 1270(3.73) |
| Rheumatoid arthritis(RA) | N.A. | 454(3.13) | 782(4.01) | 1236(3.63) |
| Gout | N.A. | 576(3.96) | 301(1.54) | 877(2.58) |
| Obesity | N.A. | 717(4.94) | 174(0.89) | 891(2.62) |
| After coronary stenting | N.A. | 101(0.7) | 220(1.13) | 321(0.94) |
| Others | N.A. | 1703(11.72) | 1633(8.37) | 3336(9.8) |
| No, n(%) | N.A. | 66,076 (81.98) | 31,541 (61.79) | 97,617 (74.15) |
*N.A. referred to “not available“.
All the participants received at least one dose of CoronaVac®, those who finished the primary immunization of two doses in children and adolescent group, adult group and elder group accounted for 90.14 % (27,979/31,041), 88.28 % (71,154/80,604) and 91.06 % (46,484/51,046), respectively.
For participants with underlying medical conditions among adults and elderly, those who received two doses of vaccinations accounted for 88.95 %(12,923/14,528) in adults and 89.98 % (17,551/19,505) for elderly. See Fig. 1 for details.
Fig. 1.
Study flowchart.
3.2. Safety
Totally there were 4,587 adverse events reported with 4,386 related to vaccines. The overall incidence of adverse reactions(ARs) was 2.70 %(4,386/162,691).
Most (99.52 %, 4,365/4,386) ARs happened within 7 days after vaccination, and those occurred with 30 min after vaccination accounted for 35.93 %(1,576/4,386). Total ARs occurred in 630 (2.03 %) of 31,041 in children and adolescents, 2,785(3.46 %) of 80,604 in adults and 971(1.90 %) of 51,046 in elderly. There was statistically significant difference among three age groups (P < 0.0001), with adult group having the highest incidence. See Table 2 for details.
Table 2.
The incidence of ARs among different age groups.
| Adverse reactions | Children and adolescents aged 3–17 years |
Adults aged 18–59 years | Adults aged 60 + years | Total | P value |
|---|---|---|---|---|---|
| n(%) | n(%) | n(%) | n(%) | ||
| Total | 630(2.03) | 2785(3.46) | 971(1.90) | 4386(2.70) | <0.0001 |
| 0–28 days | 630(2.03) | 2785(3.46) | 971(1.90) | 4386(2.70) | <0.0001 |
| 0–7 days | 626(2.02) | 2772(3.44) | 967(1.89) | 4365(2.68) | <0.0001 |
| 8–28 days | 11(0.04) | 42(0.05) | 11(0.02) | 64(0.04) | 0.023 |
| 29 days-6 months | 2(0.01) | 3(0.00) | 1(0.00) | 6(0.00) | 0.591* |
| Severity | |||||
| Grade 1 | 606(1.95) | 2673(3.32) | 943(1.85) | 4222(2.6) | <0.0001 |
| Grade 2 | 99(0.32) | 360(0.45) | 58(0.11) | 517(0.32) | <0.0001 |
| Grade 3 | 4(0.01) | 13(0.02) | 3(0.01) | 20(0.01) | 0.261* |
| Symptoms | |||||
| Solicited | 568(1.83) | 2752(3.41) | 955(1.87) | 4275(2.63) | <0.0001 |
| Systemic | 179(0.58) | 948(1.18) | 394(0.77) | 1521(0.93) | <0.0001 |
| anorexia | 17(0.05) | 63(0.08) | 19(0.04) | 99(0.06) | 0.012 |
| acute anaphylaxis | 3(0.01) | 22(0.03) | 4(0.01) | 29(0.02) | 0.018* |
| fever | 69(0.22) | 95(0.12) | 17(0.03) | 181(0.11) | <0.0001 |
| fatigue | 64(0.21) | 520(0.65) | 171(0.33) | 755(0.46) | <0.0001 |
| muscle pain | 7(0.02) | 194(0.24) | 77(0.15) | 278(0.17) | <0.0001 |
| headache | 27(0.09) | 276(0.34) | 86(0.17) | 389(0.24) | <0.0001 |
| cough | 53(0.17) | 92(0.11) | 21(0.04) | 166(0.10) | <0.0001 |
| mucocutaneous abnormality | 3(0.01) | 24(0.03) | 6(0.01) | 33(0.02) | 0.028* |
| vomiting | 13(0.04) | 45(0.06) | 21(0.04) | 79(0.05) | 0.419 |
| nausea | 24(0.08) | 150(0.19) | 81(0.16) | 255(0.16) | <0.0001 |
| diarrhea | 11(0.04) | 139(0.17) | 26(0.05) | 176(0.11) | <0.0001 |
| Local | 442(1.42) | 2107(2.61) | 654(1.28) | 3203(1.97) | <0.0001 |
| redness | 25(0.08) | 122(0.15) | 51(0.1) | 198(0.12) | 0.002 |
| pain | 383(1.23) | 1792(2.22) | 489(0.96) | 2664(1.64) | <0.0001 |
| pruritus | 14(0.05) | 161(0.2) | 68(0.13) | 243(0.15) | <0.0001 |
| rash | 19(0.06) | 123(0.15) | 22(0.04) | 164(0.10) | <0.0001 |
| induration/ swelling | 53(0.17) | 310(0.38) | 148(0.29) | 511(0.31) | <0.0001 |
| Unsolicited | 102(0.33) | 52(0.06) | 27(0.05) | 181(0.11) | <0.0001 |
Most ARs were grade 1 and grade 2 in severity, and the incidence of grade 3 ARs were 0.01 % (4/31,041) in children and adolescents, 0.02 % (13/80,604) in adults and 0.01 % (3/51,046) in elderly, respectively. Most ARs occurred within 7 days after vaccination, and only 1 occurred within 30 days after vaccination. Two children had fever or pruritus at the injection sites of grade 3, another two children had pain or pruritus at the injection sites. A total of 13 adults had ARs of grade 3 with 4 of them having UMCs; 9 of them occurred after first dose and 4 occurred after second dose. The most common symptoms included fatigue, pain at the injection sites pruritus, followed by diarrhea and cough. The symptoms of grade 3 among elderly were headache, rash, muscular pain and fatigue.
In addition, the incidence of ARs after the first dose(1.89 %, 3,079/162,691) was higher than that after the second dose (1.04 %, 1,697/162,691) (see Table S1 for details).
The incidences of solicited and unsolicited adverse reactions (ARs) are presented in Table 2. Most ARs were solicited, with the incidences in three age groups were 1.83 % (568/31,041), 3.41 % (2,752/80,604) and 1.87 % (955/51,046) (P < 0.0001). Pain at the injection sites was the most common local symptom for all three age groups, followed by induration or swelling. For children and adolescents, the most common systemic ARs were fever, followed by fatigue and cough. While for adults and elderly, fatigue was the most common systemic ARs, followed by headache and muscle pain. The incidences of solicited and unsolicited ARs were 2.82 %(3,707/131,650) and 0.06 %(79/131,650) among adults aged over 18 years old. For solicited ARs, the incidences of healthy adults and adults with UMCs were 2.77 %(2,706/97,617) and 2.94 %(1,001/34033), with no statistical significance (P = 0.106), see table 4 for details.
There were 13 serious adverse events(SAEs) reported and none of them were determined by investigators to be caused by the vaccine. No adverse events of special interest (AESIs) were identified.
For children and adolescents, children aged 3–5 years had the highest incidence of 3.29 %(185/5,631). Incidences of ARs among children aged 6–11 years and adolescents aged 12–17 years were 1.67 %(261/15,656) and 1.89 %(184/9754), respectively. Most ARs were grade 1 and pain at the injection site was the most common symptoms (see Table 3 and see Table S2 for details of symptoms and different doses).
Table 3.
The incidence of ARs among participants aged 3–17 years.
| Adverse Reactions | Children aged 3–5 years | Children aged 6–11 years | Adolescents aged 12–17 years | Total | P value* |
|---|---|---|---|---|---|
| n(%) | n(%) | n(%) | n(%) | ||
| Total | 185(3.29) | 261(1.67) | 184(1.89) | 630(2.03) | 0.000 |
| 0–28 days | 185(3.29) | 261(1.67) | 184(1.89) | 630(2.03) | 0.000 |
| 0–7 days | 183(3.25) | 260(1.66) | 183(1.88) | 626(2.02) | 0.000 |
| 8–28 days | 4(0.07) | 6(0.04) | 1(0.01) | 11(0.04) | 0.150 |
| 29 days-6 months | 0(0.00) | 2(0.01) | 0(0.00) | 2(0.01) | 0.374 |
| Severity | |||||
| Grade 1 | 178(3.16) | 251(1.60) | 177(1.81) | 606(1.95) | 0.000 |
| Grade 2 | 36(0.64) | 44(0.28) | 19(0.19) | 99(0.32) | 0.000 |
| Grade 3 | 1(0.02) | 3(0.02) | 0(0.00) | 4(0.01) | 0.399 |
| Symptoms | |||||
| Solicited | 156(2.77) | 243(1.55) | 169(1.73) | 568(1.83) | 0.000 |
| Systemic | 61(1.08) | 75(0.48) | 43(0.44) | 179(0.58) | 0.000 |
| Local | 108(1.92) | 194(1.24) | 140(1.44) | 442(1.42) | 0.001 |
| Unsolicited | 40(0.71) | 40(0.26) | 22(0.23) | 102(0.33) | 0.000 |
The incidence of ARs among those aged more than 18 years old with underlying medical conditions (UMCs) (2.81 %, 2,740/80,604) was higher than those without UMCs (2.99 %, 1016/51,046), but the difference showed no statistical significance(P = 0.089).
More systemic symptoms happened among adults and elderly with UMCs(1.26 %, 428/31541), while more local symptoms occurred among healthy adults and elderly(2.12 %, 2066/66076). See table S3 for details of different doses.
According to age, the incidences of ARs among adults with or without UMCs aged 18–59 years were 3.89 %(565/14,528) and 3.36 %(2,220/66,076), respectively, the difference between groups showed statistical significance(P = 0.002); while the incidences for elderly aged 60 years were 2.31 %(451/19,505) and 1.65 %(520/31,541), difference between groups also showed statistical significance(P < 0.0001). See Table 4 for details and see Table S4 for details of different doses.
Table 4.
Incidence of ars among adults aged more than 18 years with and without underlying medical conditions(UMCs).
| Adverse reactions |
Adults aged 18–59 years |
Adults aged 60 + years |
Total |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Healthy | With UMCs | Total | P value | Healthy | With UMCs | Total | P value | Healthy | With UMCs | Total | P value | |
| n(%) | n(%) | n(%) | n(%) | n(%) | n(%) | n(%) | n(%) | n(%) | ||||
| Total | 2220(3.36) | 565(3.89) | 2785(3.46) | 0.002 | 520(1.65) | 451(2.31) | 971(1.9) | 0.000 | 2740(2.81) | 1016(2.99) | 3756(2.85) | 0.089 |
| Solicited | 2197(3.32) | 555(3.82) | 2752(3.41) | 0.003 | 509(1.61) | 446(2.29) | 955(1.87) | 0.000 | 2706(2.77) | 1001(2.94) | 3707(2.82) | 0.106 |
| Systemic | 720(1.09) | 228(1.57) | 948(1.18) | 0.000 | 194(0.62) | 200(1.03) | 394(0.77) | 0.000 | 914(0.94) | 428(1.26) | 1342(1.02) | 0.000 |
| Local | 1701(2.57) | 406(2.79) | 2107(2.61) | 0.135 | 365(1.16) | 289(1.48) | 654(1.28) | 0.002 | 2066(2.12) | 695(2.04) | 2761(2.10) | 0.416 |
| Unsolicited | 39(0.06) | 13(0.09) | 52(0.06) | 0.205 | 19(0.06) | 8(0.04) | 27(0.05) | 0.431 | 58(0.06) | 21(0.06) | 79(0.06) | 0.898 |
| Hypertension | ||||||||||||
| Total | 2625(3.48) | 160(3.06) | 2785(3.46) | 0.117 | 766(1.90) | 205(1.90) | 971(1.90) | 1.000 | 3391(2.93) | 365(2.28) | 3756(2.85) | 0.000 |
| Solicited | 2597(3.45) | 155(2.97) | 2752(3.41) | 0.070 | 752(1.87) | 203(1.88) | 955(1.87) | 0.968 | 3349(2.90) | 358(2.23) | 3707(2.82) | 0.000 |
| Systemic | 884(1.17) | 64(1.23) | 948(1.18) | 0.740 | 312(0.78) | 82(0.76) | 394(0.77) | 0.902 | 1196(1.03) | 146(0.91) | 1342(1.02) | 0.154 |
| Local | 1997(2.65) | 110(2.11) | 2107(2.61) | 0.017 | 520(1.29) | 134(1.24) | 654(1.28) | 0.700 | 2517(2.18) | 244(1.52) | 2761(2.10) | 0.000 |
| Unsolicited | 16(0.02) | 4(0.08) | 20(0.02) | 0.037 | 9(0.02) | 2(0.02) | 11(0.02) | 1.000 | 25(0.02) | 6(0.04) | 31(0.02) | 0.263 |
| Diabetes | ||||||||||||
| Total | 2721(3.46) | 64(3.36) | 2785(3.46) | 0.899 | 898(1.89) | 73(2.13) | 971(1.9) | 0.300 | 3619(2.86) | 137(2.57) | 3756(2.85) | 0.223 |
| Solicited | 2691(3.42) | 61(3.20) | 2752(3.41) | 0.655 | 883(1.85) | 72(2.1) | 955(1.87) | 0.296 | 3574(2.83) | 133(2.50) | 3707(2.82) | 0.163 |
| Systemic | 925(1.18) | 23(1.21) | 948(1.18) | 0.830 | 360(0.76) | 34(0.99) | 394(0.77) | 0.129 | 1285(1.02) | 57(1.07) | 1342(1.02) | 0.676 |
| Local | 2064(2.62) | 43(2.25) | 2107(2.61) | 0.345 | 610(1.28) | 44(1.29) | 654(1.28) | 0.937 | 2674(2.12) | 87(1.63) | 2761(2.1) | 0.015 |
| Unsolicited | 49(0.06) | 3(0.16) | 52(0.06) | 0.125 | 25(0.05) | 2(0.06) | 27(0.05) | 0.702 | 74(0.06) | 5(0.09) | 79(0.06) | 0.254 |
| Chronic Gastritis(CG) | ||||||||||||
| Total | 2706(3.45) | 79(3.82) | 2785(3.46) | 0.360 | 939(1.9) | 32(2.11) | 971(1.9) | 0.505 | 3645(2.85) | 111(3.10) | 3756(2.85) | 0.360 |
| Solicited | 2673(3.40) | 79(3.82) | 2752(3.41) | 0.297 | 923(1.86) | 32(2.11) | 955(1.87) | 0.442 | 3596(2.81) | 111(3.10) | 3707(2.82) | 0.306 |
| Systemic | 912(1.16) | 36(1.74) | 948(1.18) | 0.022 | 377(0.76) | 17(1.12) | 394(0.77) | 0.133 | 1289(1.01) | 53(1.48) | 1342(1.02) | 0.009 |
| Local | 2048(2.61) | 59(2.85) | 2107(2.61) | 0.485 | 634(1.28) | 20(1.32) | 654(1.28) | 0.817 | 2682(2.09) | 79(2.2) | 2761(2.1) | 0.636 |
| Unsolicited | 52(0.07) | 0(0.00) | 52(0.06) | 0.646 | 27(0.05) | 0(0.00) | 27(0.05) | 1.000 | 79(0.06) | 0(0.00) | 79(0.06) | 0.282 |
| Coronary heart disease(CHD) | ||||||||||||
| Total | 2755(3.44) | 30(6.34) | 2785(3.46) | 0.001 | 872(1.77) | 99(5.54) | 971(1.9) | 0.000 | 3627(2.8) | 129(5.71) | 3756(2.85) | 0.000 |
| Solicited | 2724(3.40) | 28(5.92) | 2752(3.41) | 0.005 | 856(1.74) | 99(5.54) | 955(1.87) | 0.000 | 3580(2.77) | 127(5.62) | 3707(2.82) | 0.000 |
| Systemic | 930(1.16) | 18(3.81) | 948(1.18) | 0.000 | 345(0.70) | 49(2.74) | 394(0.77) | 0.000 | 1275(0.99) | 67(2.96) | 1342(1.02) | 0.000 |
| Local | 2093(2.61) | 14(2.96) | 2107(2.61) | 0.564 | 593(1.20) | 61(3.41) | 654(1.28) | 0.000 | 2686(2.08) | 75(3.32) | 2761(2.10) | 0.000 |
| Unsolicited | 50(0.06) | 2(0.42) | 52(0.06) | 0.038 | 26(0.05) | 1(0.06) | 27(0.05) | 0.618 | 76(0.06) | 3(0.13) | 79(0.06) | 0.155 |
| Kidney stone | ||||||||||||
| Total | 2720(3.44) | 65(4.3) | 2785(3.46) | 0.075 | 958(1.90) | 13(2.27) | 971(1.90) | 0.536 | 3678(2.84) | 78(3.74) | 3756(2.85) | 0.017 |
| Solicited | 2688(3.40) | 64(4.24) | 2752(3.41) | 0.085 | 942(1.87) | 13(2.27) | 955(1.87) | 0.437 | 3630(2.80) | 77(3.69) | 3707(2.82) | 0.019 |
| Systemic | 924(1.17) | 24(1.59) | 948(1.18) | 0.146 | 389(0.77) | 5(0.87) | 394(0.77) | 0.634 | 1313(1.01) | 29(1.39) | 1342(1.02) | 0.098 |
| Local | 2058(2.6) | 49(3.24) | 2107(2.61) | 0.122 | 644(1.28) | 10(1.75) | 654(1.28) | 0.344 | 2702(2.09) | 59(2.83) | 2761(2.10) | 0.025 |
| Unsolicited | 51(0.06) | 1(0.07) | 52(0.06) | 0.626 | 27(0.05) | 0(0.00) | 27(0.05) | 1.000 | 78(0.06) | 1(0.05) | 79(0.06) | 1.000 |
The incidences of ARs among participants with or without top 5 UMCs(hypertension, diabetes, chronic gastritis, coronary heart disease(CHD) and kidney stone) according to age(18–59 years v.s. 60 years and above) were shown in Table 4 and Table S5-S9. Differences between healthy participants and participants with hypertension, diabetes, chronic gastritis, and kidney stone showed no statistical significance in both age groups. Results indicated that participants with CHD had the highest incidence of ARs, which was 5.71 %(129/2,260), with incidences among adults and elderly being 6.34 %(30/473) and 5.54 %(99/1,787), respectively. The most common symptom was pain at the injection site.
4. Discussion
In our study, a total of 162,691 participants were included. 89.5 % of them finished the primary immunization. CoronaVac® is safe in a large-scale use and shows well-tolerance for children and adolescents and people with underlying medical conditions. Most ARs were grade 1 in severity and the most common ARs among participants with UMCs was pain at the injection site.
Adults had the highest incidence of ARs while elderly had the lowest incidence. For children and adolescents, children aged 3–5 years had higher incidence. As a whole, the difference of ARs among healthy people and people with underlying medical conditions(UMCs) showed no statistical significance. When analyzing the differences between healthy adults and adults with UMCs according to age(18–59 years v.s. 60 years and above), we found that differences between adults with or without hypertension, diabetes, chronic gastritis, and kidney stone showed no statistical significance in both age groups. Although the incidence of ARs among participants with coronary heart disease was significantly higher than healthy participants for both adults and elderly, the symptoms that caused incidence differences were all solicited.
In this study, the proportions of children and adolescent group, adult group and elder group who received two doses of CoronaVac® were 90.14 %, 88.28 % and 91.06 %, respectively. The reason for lower vaccination coverage of adults may be the immigration to other cities or provinces for work or the compliance in terms of education background, which led to the loss to follow-up. For participants with underlying medical conditions among adults and elderly, those who received two doses of vaccinations accounted for 88.95 %(12,923/14,528) in adults and 89.98 % (17,551/19,505) for elderly.
A meta-analysis of RCTs that pooled incidences of Adverse Events Following Immunization(AEFI) for inactivated vaccines and gave an incidence of 23.0 %[4], which was higher than the result of our study. Studies showed that reporting rates of common AEFI after mass public vaccination were lower than in clinical trials[16]. Considering the difference of study design and safety monitoring frequency, we thought our results reasonable. Besides, we found our results similar to results of other similar real-world studies. A systematic review of various SARS-CoV-2 vaccines showed an overall pooled incidence rate of 1.50 % for adverse events [3]. And another study carried out during the emergency use of two inactivated SARS-CoV-2 vaccines among special population such as health care workers at medical institutions and front-line workers at the Centers for Disease Control and Prevention(CDC) gave an in incidence of 1.06 % [17]. However, considering other inactivated vaccines, such as in inactivated enterovirus 71(EV71) vaccine, the overall incidence of ARs ranged from 1.08 % to 3.31 %[18], [19], [20]. The overall incidence of ARs in this study was 2.7 %, with no SAE or AESI that caused by vaccines observed. Thus, we consider our study giving a well-tolerated overall incidence of adverse reactions, which indicated that CoronaVac® is safe to use among population aged 3 years old and above in a large-scale.
In our study, most ARs were solicited and grade 1 or 2 in severity, and most occurred within 7 days after vaccination, these were similar to the results of most studies[4], [5], [11], [12], [13], [14], [15], [16], [3], [17].
In terms of the symptoms, pain at the injection sites was the most common local symptoms, the most common systemic ARs for children and adolescents were fever, fatigue and cough. While for adults and elderly, fatigue was the most common systemic ARs, followed by headache and muscle pain, these were consistent with RCTs studies in phase Ⅰ/Ⅱ/III[11], [12], [13], [14], [15]. A review synthesized the safety data of published RCTs found that COVID‐19 vaccines have shown good safety in children and adolescents, with the most common local and systemic injection‐site pain, fever, headache, cough, fatigue, and muscle pain[5]. Another study focused on the safety of vaccination among children and adolescents showed that injection-site pain, fatigue, and headache were the top three adverse events after each dose of SARS-CoV-2 vaccines[21]. In our study, similar results were observed.
A study exploring the impact of age difference on the efficacy and safety of COVID-19 vaccines indicated a higher incidence of local and systemic AEs in young people than in the elderly with an OR of 1.10[22]. Another study showed similar results, that adolescents had the highest incidence(11.31 %), followed by adults aged 30 to 39 years old(1.18 %), and elderly aged over 60 years old had the lowest incidence(0.32 %), differences of age groups also showed statistical significance[17]. In our study, adults had the highest incidence of ARs and elderly had the lowest incidence, which was consistent with the results of clinical trials of phase 3[16], [23]. In our study, the adverse events were collected mainly by interviews or phone calls of investigators among elderly people, while most adults used smart phones. This may have a little influence on the incidence but would not have major effect on study results, further studies were needed to figure out the incidence of adverse events among different age groups.
A study conducted among adults aged 40 years and older with UMCs(coronary artery disease (CAD), hypertension, diabetes, chronic respiratory disease (CRD), obesity and cancer) showed the incidences of ARs for healthy participants and those with UMCs were 13.97 % and 20.27 %. Most adverse events were mild (grade 1) in severity and the most frequently reported reactions were injection-site pain in both healthy and UMCs groups[24]. Our study had similar results that the incidence of ARs among people with UMCs was higher than it among healthy people, but the incidences were lower in this study. Besides, our study analyzed the differences between healthy participants and participants with different UMCs according to age(18–59 years v.s. 60 years and above), only differences between healthy participants and participants with CHD showed a statistical significance in both age groups. These may related to the self-attention of participants with UMCs, especially for people with chronic cardiovascular disease. Since few studies focused on the vaccine safety of vaccines among people with UMCs, further studies were still needed.
In this study, we used data collection system that made information collection more convenient without less delay. Furthermore, our results were similar to other studies using diary cards, which indicated the data collection system were reliable and can be used to studies with large samples. Still further comparison with diary cards will need to be further explored.
CoronaVac® is safe and well-tolerated to use among population aged 3 years and older and those with underlying medical conditions in post-market large-scale use. The incidence of adverse events in long-term will still be collected until this study ends. Our results indicated that the incidence of ARs among UMCs may be influenced by age, thus further studies may still need to explore the relations of incidence to age or UMCs.
This study had two limitations. First, our study used a passive method to collect safety information of vaccination, factors such as the compliance of participants or the immigration of adults for work may led the loss of follow-up. Secondly, our study using data collection system that differed from diary cards to collect safety information, the comparison will need to be further explored.
Author contributions
Z.L., H.Y., Y.G., and X.L. contributed to the conception and design of the protocol. H.Y., R.Z., S.G., B.W., X.F., D.Z., X.Z., Y.T., Q.W., Q.D., and Z.S. conducted the clinical trial and quality control. Z.L. supervised the clinical trial and contributed to manuscript drafting. Additionally, all authors revised the work, approved the submitted version of the paper, and agreed to be accountable for all aspects of the work.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.vaccine.2023.01.020.
Appendix A. Supplementary data
The following are the Supplementary data to this article:
Data availability
The data that has been used is confidential.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that has been used is confidential.