ABSTRACT
Objectives
To summarize reports to the national adverse event following immunization surveillance system (NAEFISS) following inactivated quadrivalent influenza vaccine (QIV) in Zhejiang province from 2018 to 2020.
Methods
We analyzed adverse events following immunization (AEFI) reports following QIV, with a comparison, with the AEFI reports following inactivated trivalent influenza vaccine (TIV). Reporting rates of AEFI were calculated by age, severity of AEFI, categories of AEFI, and reaction categories. The data mining algorithm used in this study was reporting odds ratio (ROR). A value of ROR‑1.96SE >1 (standard error [SE]) was considered as positive signal. These reporting rates between vaccine types were compared through chi-square tests.
Results
NAEFISS received 514 AEFI reports following QIV and 536 reports following TIV, with a reporting rate of 13.66/100,000 100,000 doses/100,000 doses (χ2 = 7.11, P> .05). Of the 514 reports following QIV, 410 were vaccine product-related reactions and 51 were severe AEFI. Fever/redness/induration was the most frequent clinical diagnosis of the QIV AEFI, with a reporting rate of 12.42/100,000 doses in the age group of 3–17 years, and 12.44/100,000 doses in the age group of ≥18 years. The positive signal of QIV AEFI was observed for the allergic rash and asthma/wheezing.
Conclusion
The present analysis did not identify any new/unexpected safety concerns. We suggested that NAEFISS continue to monitor the safety of QIV.
Introduction
Influenza is associated with a significant burden on public health system, causing 25–50 million patients and leading to 150,000 hospitalizations and 40,000 deaths in every year worldwide.Citation1 Three virus strains circulate and cause the infections or seasonal epidemics each year, including influenza A/H3N2, influenza A/H1N1, and influenza B.Citation2 Although influenza A often is responsible for the most infections for each year, influenza B causes the seasonal epidemics every 2–4 years.Citation3 The influenza B is also known as the main cause of the serious infections resulting in hospitalization among young children.Citation4,Citation5
Two genetically distinct lineages of influenza B, known as influenza B/Victoria and influenza B/Yamagata, co-circulate globally.Citation6 The World Health Organization (WHO) annually recommends the seasonal trivalent influenza vaccine should contain the antigens against two strains of influenza A and one strain of influenza B, which are selected annually by an expert panel according to the surveillance of influenza virus.Citation7 Recently, quadrivalent influenza vaccine, which includes two strains of influenza A and both influenza B/Victoria and influenza B/Yamagata, has been developed as the live attenuated and the inactivated formations.Citation8,Citation9
GGGA number of randomized controlled trials had illustrated the safety of quadrivalent influenza vaccine in adults and children,Citation10–13 as well as two post-licensure surveillance reports of adverse events following immunization (AEFI) for the live attenuated quadrivalent influenza vaccine.Citation14,Citation15 However, post-licensure AEFI surveillance for inactivated quadrivalent influenza vaccine (QIV), with comparison to the inactivated trivalent influenza vaccine (TIV) are limited. In 2018, the domestic QIV was approved by the China Food and Drug Administration and was introduced to the private market as a self-paid vaccine in Zhejiang province in the same year. In pre-licensure clinical trials, most of the solicited AEFI following the domestic QIV were fever, redness, and pain on the site of injection (≥10%). According to the package insert of the domestic QIV, healthy persons aged ≥3 years who have no contraindications or precautions are recommended to receive one dose during an influenza season. It is not recommended for persons with certain underlying medical conditions.
These aforementioned studies covered reports only from the pre-licensure of QIV. Many new AEFIs may have unfolded due to the wide application of the domestic QIV, which would result in an ambiguous profile on the safety. It was the goal of this study to summarize and characterize the AEFI reports following the domestic QIV reported to the national adverse event following immunization surveillance system (NAEFISS) from 2018 to 2020, as compared to the AEFI reports of TIV. We hoped to provide the updated safety information and assess the rare AEFIs more recently emerged to allege the safety concerns of the domestic QIV after its licensure.
Methods
1. Study area
Zhejiang province has a dense population of 70 million and is located at the east coastline of China. The Chinese expanded program on immunization (CEPI) was initiated in 1978, and 11 vaccines were added in to the CEPI up to date. More than 25 million vaccination doses were administrated for children, adolescents, and adults each year in Zhejiang province.
2. Study design
We conducted a descriptive analysis of NAEFISS data, for calculating the reporting rates of AEFI of QIV and TIV used in Zhejiang province, based on the vaccine doses of influenza vaccines as well as the other vaccines used in Zhejiang province during the same period. We compared the reporting rate of QIV with TIV as well as with the other kinds of vaccines, to identify the reporting rate of QIV whether higher than that of TIV and the other licensed vaccines or not.
3. Data source
NAEFISS is a national spontaneous reporting system for monitoring AEFI. The NAEFISS was established in 2005 and was upgraded in 2012, adding variables of the case reporting form and rules of data logic verification.Citation16 Zhejiang province has joined in the NAEFISS since 2009. NAEFISS accepts reports from vaccine manufacturers, vaccination providers, recipients, and others. NAEFISS data includes the demographic information of the recipients, vaccine type, the symptoms or diagnosis of AEFI. The symptoms or diagnosis of AEFI is coded using international classification of diseases (version 10.0, ICD-10),Citation17 a clinically validated, internationally standardized terminology. A single AEFI report may be assigned more than one term and be referred to more than one suspected vaccine.
The AEFI reports of QIV and TIV from 2018 to 2020 were obtained from the NAEFISS on May 1, 2021, to account for data lags due to the correction and cleaning. The number of doses of QIV and TIV and the other vaccines used in Zhejiang province during the same period was extracted from the online immunization information system of Zhejiang province (ZJIIS), which was established in 2005 and its functions could be found elsewhere.Citation18
4. Category of AEFI
All AEFI reports were divided into five categories according to the guidelines on AEFI surveillance issued by the China center for disease control and prevention (China CDC):Citation19 (1) vaccine product-related reaction (minor or severe); (2) vaccination error; (3) vaccine quality defect-related reaction; (4) coincidental event; (5) anxiety reaction. Severity of AEFI is assessed as minor or severe:Citation19 (1) AEFI reports with no intervention necessary or with physician visit or event interfering with daily activities or loss of working hours are defined as minor; and (2) AEFI reports with any untoward medical occurrence that results in death, hospitalization, prolongation of hospitalization, persistent, or significant disability/incapacity, life threatening, or birth defect are defined as severe.
5. Outcome and data analysis
Data were collated as an Excel file (Microsoft Office Excel 2020) and exported to Stata 14.0 (Stata Corp. 2015, Stata statistical software, college station, TX, USA) for analysis. Descriptive statistics of AEFI reports, including patient age, gender, the clinical diagnosis, the AEFI onset interval (from vaccination date [day 0] to onset of first symptoms), AEFI categories, severity, and type of reporter, were calculated and presented by percentages or reporting rates when appropriate. The reporting rate was calculated through dividing the number of AEFI reports by the relevant vaccine doses administered. These reporting rates between vaccine types were compared through chi-square tests at a two-tail significance of 0.05.
Disproportionality analysis was applied by using the algorithm of reporting odds ratio (ROR).Citation20 The ROR is the ratio of the odds of reporting of one specific AEFI versus all other AEFIs for a given vaccine compared to the reporting odds for all other vaccines present in the database. Generally, a value of ROR‑1.96SE >1 (standard error [SE]) is considered as a cutoff value and it is considered as a positive signal if the ROR above the threshold value. The higher the value, the stronger the disproportion appears to be. The positive signal meant that the reporting rate of QIV was higher than the average level of the other vaccines.
We performed a clinical review of some interest AEFI reports for QIV, including Guillain–Barré Syndrome (GBS), febrile convulsion, anaphylaxis, asthma/wheezing. As a part of routine AEFI investigation procedure, medical records were requested for all severe reports, which were reviewed by the physicians with expertise in vaccine safety. For the death case report, autopsy reports and death certificates were required to determine the cause of death.
Results
1. Reporting characteristics
During the three influenza seasons from 2018 to 2020, NAEFISS received 514 AEFI reports following QIV (3,762,337 doses administered) and 536 reports following TIV (4,095,522 doses administered), with a reporting rate of 13.66/100,000 doses and 13.09/100,000 doses (χ2 = 7.11, P> .05), respectively. Of the 514 reports following QIV, 410 were vaccine product-related reactions (10.90/100,000 doses) and 51 (48 were considered product-related) were severe AEFI (1.36/100,000 doses). Of the 536 reports following TIV, 427 were vaccine product-related reactions (10.43/100,000 doses) and 59 were severe AEFI (1.44/100,000 doses). Of the received AEFI reports, most were reported by patients or caregivers (80.00%), and 76.86% occurred in 24 hours after vaccination. Over the half of the patients (59.24%) were ≥50 years old and 97.14% of recipients received the QIV or TIV without co-administration with other vaccines. The characteristics of the AEFI reports were not significantly different between QIV and TIV recipients ().
Table 1. AEFI reporting rate of QIV and TIV in Zhejiang province from 2018 to 2020
Table 2. Characteristics of AEFI reports of QIV and TIV in Zhejiang province from 2018 to 2020
2. Clinical characteristics and disproportionality analysis
summarized the clinical reviews of AEFI reports following QIV by age group, with reports following TIV as a comparator. There was no death report identified both in the QIV and TIV recipients.
Table 3. Clinical diagnosis of AEFI reports of QIV and TIV in children and adolescent aged 3–17 years from 2018 to 2020
Table 4. Clinical diagnosis of AEFI reports of QIV and TIV in adults ≥18 years from 2018 to 2020
Among the age group of 3–17 years, fever/redness/induration was the most frequent clinical diagnosis in both QIV and TIV recipients, with a reporting rate of 12.42/100,000 doses and 12.27/100,000 doses, respectively. The reporting rate of the other reactions ranged 0.08–0.39/100,000 doses and the reporting rates of all QIV AEFIs were not significantly different with those of TIV AEFIs. The positive signal of QIV AEFI was observed for the allergic rash (ROR‑1.96SE: 1.52).
In the age group of ≥18 years, fever/redness/induration was the most frequent clinical diagnosis in both QIV and TIV recipients, with a reporting rate of 12.44/100,000 doses and 11.39/100,000 doses, respectively. The reporting rate of the other reactions ranged 0.04–0.32/100,000 doses and the reporting rates of all QIV AEFIs not significantly different with those of TIV AEFIs. The positive signals of QIV AEFI were observed in the asthma/wheezing (ROR‑1.96SE: 1.26) and the allergic rash (ROR‑1.96SE: 1.42).
4. Clinical review
Two reports of GBS following QIV were identified and two cases received the QIV alone. One involved a 15-year-old male with a history of croup during infancy, recurrent otitis media. This patient developed the neurologic symptoms 16 days following vaccination. The second case involved a 63-year-old female without a clear health history and developed the neurologic symptoms 9 days following vaccination. Neither case had a recent respiratory or gastrointestinal infection before the QIV vaccination.
Five febrile convulsion reports following QIV were identified, of which four were under 18 years old and one was ≥18 years. Three of them were female and the symptoms occurred 2 days following vaccination, while the symptoms occurred on the day of vaccination for the other two reports. None of them required an emergency room visit and recovered by the time of submitting the report to the NAEFISS.
Two acute anaphylaxis reports, including one anaphylactic shock in a 26-year-old male and one angioedema in a 15-year-old male, were identified. Two cases had a history of food allergies (peanuts and mango) and the symptom onset began approximately 17 and 23 minutes after administering the vaccine, respectively. Both of them were assigned to the emergency room and treated with epinephrine, and discharged home after the medical observation for 24 hours.
Four cases of asthma/wheezing identified had a history of asthma or reactive airway disease and all of them were ≥50 years of age. All four patients were categorized as minor, and their wheezing episodes included other symptoms, like nasal congestion or sinus pain.
Discussion
Our review of NAEFISS reports following QIV from its initial influenza season of use found no significant difference in the safety compared to TIV, and did not identify any new or unexpected safety concerns. Our findings represented the first post-licensure evaluation of safety of QIV and added to the existing evidence on safety profile from the pre-licensure clinical trials. Just over 90% of AEFI reports following QIV were minor and the most common adverse events were mild, self-limited conditions (e.g., fever, redness, and induration).
In this study, most of the AEFI reports were submitted by health-care provider or patients/caregivers, which could improve the reporting quality as more information would be collected. More sufficient identifying information might allow the following medical review of each cases and induce a confirmed category of AEFI. As expected, over half of the AEFI reports following QIV or TIV were among the age group of ≥50 years, which was also the age group of the higher vaccination coverage of influenza vaccines.Citation21–23 Most of AEFI occurred on the day of vaccination, which was similar to the results from our previous report on the surveillance on AEFI for all vaccines used in Zhejiang province.Citation19 The minor adverse reactions, such as fever and rash, were very common following influenza vaccines as well as the other vaccines.Citation24 As we known, the onset interval for these common adverse reactions were generally very short.
From clinical review of the interest AEFI reports, we identified two GBS reports, with the symptom onset within the 42-day window of biological plausibility. GBS is an acute, immune-mediated demyelinating disorder of the peripheral nervous system that has been inconsistently associated with inactivated influenza vaccines.Citation25 A report from the passive adverse event surveillance in U.S. suggested an unusually large number of reports of GBS in 1976.Citation26 A subsequent case-control study demonstrated a statistically significant increase in the risk of developing GBS in 6 weeks following vaccination with this swine influenza vaccine.Citation27 Despite of the strong epidemiologic data in this report, the biologic mechanisms remained unclear. Subsequent studies assessing risk of GBS following other formulations of influenza vaccine had failed to consistently demonstrate a more than marginal increased risk of GBS.Citation28 Also, in this study, our data mining analysis did not detect an increased proportional reporting of GBS following QIV compared with other vaccines.
Five reports of febrile convulsion under 18 years old were observed. All could be classified as simple, which recovered in a short time and was not associated with focal neurologic findings or not recurred. A febrile convulsion is a seizure occurring in a child 6 months to 5 years old that is accompanied by a fever (≥38°C) without central nervous system infection. The cause of febrile convulsion is multifactorial, such as viral illnesses, certain vaccinations, and genetic predisposition. Febrile convulsion can be induced under the stress of a fever.Citation29 There had been some controversy on the association between vaccination and febrile convulsion, although vaccination was found to be the second common cause.Citation30–34 Our data mining analysis failed to detect increased proportional reporting of febrile convulsion following QIV. We speculated that other factors, such as age, genetic inheritance and the timing of vaccination would complex the relationship between febrile convulsion and vaccination.
We found two anaphylaxis reactions following QIV in this study, including one angioedema and one anaphylactic shock, which might be causally associated with the QIV vaccination. Anaphylaxis implies the previous exposure and sensitization to the triggering substance or a cross-reactive allergen. In previous studies, the reporting rate of anaphylaxis following vaccination was in the range of 1–10/1 million doses,Citation35,Citation36 which was similar to our findings. Moreover, the reporting rate of anaphylaxis following QIV was not significant different with that for TIV and was not detected as a positive signal. According to the Chinese immunization regulation, we still urged that all vaccination providers should require the recipients for the 30-min medical observation after vaccination to prevent these life-threatening events.
Our study identified asthma and/or wheezing cases in persons aged ≥50 years. It was also detected as a positive signal. Asthma and/or wheezing are more likely to occur in persons with a history of asthma and/or reactive airway disease.Citation37 The association between vaccination and asthma and/or wheezing has currently not been established and the mechanism of asthma and/or wheezing following vaccination has also currently not been understood. Hence, the manufacturer’s package insert for QIV contains a statement in the Warning and Precautions section that “ … persons of any age with asthma may be at increased risk of wheezing following the administration.” Another observed positive signal was allergic rash, which was reported as a common clinical manifestation of the hypersensitivity reactions. The main reason would be the recipient was allergic to the components of the vaccine, like proteins.
There were still several limitations regarding this study. The passive surveillance in general had some limitations, such as underreporting, incomplete information, varying quality of reports, and lack of an unvaccinated comparison group. Second, signals detected based on the passive surveillance data of AEFI should be used simultaneously with the medical judgment and the pharmacological evidence. As a national surveillance system, NAEFISS could rapidly detect the rare AEFIs and the potential vaccine safety problems, which could be further explored in carefully designed epidemiological studies.
Conclusion
Our review of QIV safety was reassuring the assessments from the pre-licensure clinical trials and was consistent with the data of TIV, since we did not identify any new/unexpected safety concern in the AEFI reports to NAEFISS from 2018 to 2020. Our findings would serve as a reference for discussing the benefits and risks of the QIV vaccination. We suggested that NAEFISS continue to monitor the safety of QIV, which became increasingly important when China CDC preferentially recommended the use of QIV.
Author contributions
HK.L. and XJ. P conceived and designed the experiments; Y.H. and XJ. P performed the experiments; H. L. and Y.W. analyzed the data; Y.W. contributed reagents/materials/analysis tools; Y.H. wrote the paper.
Disclosure of potential conflicts of interest
The authors declare that they have no competing interests.
Ethics approval and consent to participate
The data reported in this study were collected under the routine public health quality assurance surveillance, thus, it was not subject to institutional review board review and informed consent requirements.
Acknowledgments
We are grateful to all physicians in all health centers for providing AEFI reports in Zhejiang province.
Additional information
Funding
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