FormalPara Key Summary Points

VaxigripTetra® (Sanofi), quadrivalent inactivated split-virion influenza vaccine (QIV), is now licensed for immunization against seasonal influenza in individuals aged ≥ 6 months in South Korea.

A multicenter, observational, active safety surveillance study of QIV administered to children aged 6–35 months in routine clinical practice was undertaken to comply with South Korean licensure requirements.

QIV had an acceptable safety profile in children aged 6–35 months and was well tolerated.

There were no safety concerns identified, confirming the safety profile of QIV in young South Korean children in routine clinical practice.

Introduction

The global burden of influenza in children aged under 5 years is substantial, with estimates prior to the COVID-19 pandemic suggesting 109.5 million influenza virus episodes and about 870,000 associated hospitalizations in 2018 alone [1]. Moreover, 28,000–111,500 deaths annually in these young children may be attributable to influenza [2]. In South Korea, seasonal influenza is typically associated with a range of about 500–5300 excess deaths across all age groups annually, and a mortality rate of 2.0–18.8 per 100,000 people [3,4,5]. The World Health Organization (WHO) recommends that annual influenza vaccination be considered for children, in addition to other groups at risk of severe influenza-associated disease and death, and healthcare workers [6].

The quadrivalent inactivated split-virion influenza vaccine (QIV), VaxigripTetra® (Sanofi), was licensed for immunization against seasonal influenza in those aged ≥ 3 years in South Korea in June 2017. The inclusion of an additional influenza B strain in QIV relative to trivalent influenza vaccines offers broader protection against seasonal influenza, with comparable safety and immunogenicity [7, 8]. Subsequently, the indicated age for QIV was lowered a year later (June 2018) to include those aged ≥ 6 months. Two post-marketing surveillance studies were undertaken to assess the safety of QIV in routine clinical practice to comply with South Korean licensure requirements [9]. The first study (GQM13) was conducted in participants aged ≥ 3 years in line with the initial indicated age group and has been published [10]. Here, we describe the second post-marketing safety surveillance study (GQM15) in the new indicated age group, children aged 6–35 months.

Methods

Study Design/Participants

This was an open, multicenter, observational study which conducted active safety surveillance for QIV (VaxigripTetra®, Sanofi) between 15 June 2018 (date of approval for the extended indication) and 14 June 2022. The study took place under conditions of routine clinical practice at 12 sites in South Korea, using similar methodology as described in the first post-marketing safety surveillance study of QIV in individuals aged ≥ 3 years (GQM13) [10]. Briefly, in the current study, children aged 6–35 months who had received a single dose of QIV according to the approved local product labeling, during a routine healthcare visit were enrolled. Children who had participated (within 4 weeks preceding enrollment) or had planned participation in another clinical study (while in the current study) were excluded. No vaccine was provided specifically for this study, and participants were enrolled after receipt of QIV as part of routine vaccination. Enrolled participants were followed up for 21–28 days after vaccination. The children may have received two doses of influenza vaccine, depending on their previous vaccination history and, if so, were only followed after one dose (either first or second vaccination).

The study was undertaken in compliance with the International Conference on Harmonization (ICH) guidelines for Good Clinical Practice and the principles of the Declaration of Helsinki. The protocol and amendments were approved by applicable independent ethics committees/institutional review boards and the regulatory agency as per local regulations. Signed informed consent from the parent or the child’s legal representative was required before inclusion in this study.

Safety Surveillance

The parents or child’s legal representatives were given diary cards, digital thermometers, and flexible rulers, and instructed how to use these to record body temperature, and solicited adverse reactions (injection site and systemic reactions) and unsolicited adverse events (AEs), including their intensity (grade 1–3), and any action taken to treat them. Solicited adverse reactions were recorded up to 7 days after vaccination, with the list of solicited reactions adjusted by age group as per the ICH E11 definitions for infants/toddlers (≤ 23 months) and children (≥ 24 months) [11]. For solicited injection site reactions, these were induration (for those aged ≤ 23 months only), ecchymosis, erythema, pain, and swelling. For solicited systemic reactions, these were crying, decreased appetite, irritability, pyrexia, somnolence, and vomiting in those aged ≤ 23 months; and chills, headache, malaise, myalgia, and pyrexia in those aged ≥ 24 months.

Unsolicited non-serious AEs that occurred up to 21–28 days after vaccination were recorded in a separate space within the diary card, along with their size or intensity (grade 1–3) and any action taken to manage them. Serious adverse events (SAEs) were reported to the study investigators as and when they occurred throughout the study. The investigator assessed the causal relationship between the vaccine and each unsolicited non-serious AE and SAE (as per the South Korean Ministry of Food and Drug Safety [MFDS] guidelines).

Statistical Analysis

No statistical hypothesis was tested. The sample size justification and data analyses are the same as those described in the previous QIV safety surveillance study (GQM13) [10]. All data analyses were descriptive and performed on the safety analysis set, defined as participants who had regardless of their vaccination schedule received a dose of QIV. The sample size was based on the need to ensure at least 600 participants (600 vaccinations) would be evaluable, in accordance with South Korean MFDS guidelines. Assuming a 10% attrition rate for loss to follow-up or for invalid or incomplete case report forms, then 670 eligible participants were required to give a probability of 95% of observing any AE (at least one occurrence) with a true incidence of 0.45% or more, using the rule of three.

The data were summarized by number and percentage (and 95% confidence intervals, CIs) of participants reporting each safety event, with 95% CIs calculated using the exact binomial distribution (Clopper–Pearson method) for proportions and the normal approximation for quantitative data. Statistical assessments were performed with SAS version 9.2 or above (SAS Institute, Cary, NC, USA).

Results

Study Participants

A total of 682 participants were enrolled in the study (median 50 per center, range 6–209), six (0.9%) of whom were excluded from the safety analysis set: five received the study vaccine prior to the site initiating contract date, and one participant was lost to follow-up. Thus, 676 (99.1%) participants were included in the safety analysis set: 450 (67%) aged ≤ 23 months, and 226 (33%) aged ≥ 24 months. The participants demographics at baseline are summarized in Table 1.

Table 1 Demographic characteristics: safety analysis set (N = 676)
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Safety

The frequency of solicited adverse reactions and unsolicited non-serious AEs are summarized in Table 2. Injection site pain was the most frequently reported solicited injection site reaction in both the ≤ 23-month (12.2% [n = 55]) and ≥ 24-month (15.5% [n = 35]) age groups. Pyrexia and somnolence were the most frequently reported solicited systemic reactions in the ≤ 23-month age group (6.0% [n = 27] each), with malaise the most frequently reported in the ≥ 24-month age group (10.6% [n = 24]). The vast majority of solicited reactions (95.5% [322/337 events]) were reported 0–3 days after vaccination. There were six grade 3 solicited injection site and systemic reactions reported in five participants (pyrexia, n = 3; erythema, n = 1; irritability, n = 1; chills, n = 1). All participants recovered by day 7 after vaccination.

Table 2 Solicited reactions by age group: safety analysis set
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Overall, 339 unsolicited non-serious AEs were reported from 208 (30.8%) participants; nasopharyngitis was the most frequently reported with 103 nasopharyngitis events reported by 95 (14.1%) participants (Table 3). Pyrexia was the only grade 3 unsolicited non-serious AE (three events in three participants), and all participants recovered. Nearly all unsolicited non-serious AEs (98.8% [335/339 events]) were considered “unlikely” to be related to QIV. The four events considered to have a “possible” causal relationship with QIV were urticaria (n = 2), nasopharyngitis (n = 1) and rhinorrhea (n = 1). There were no SAEs or AEs leading to study termination reported.

Table 3 Unsolicited adverse events: safety analysis set
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Discussion

This post-marketing safety surveillance study confirms the safety of QIV in children aged 6–35 months in routine clinical practice in South Korea. No safety issues were identified, and no SAEs or AEs leading to study termination were reported during the 4-year surveillance period. The most frequently reported solicited reactions were injection site pain, pyrexia, somnolence, and malaise, and nasopharyngitis was the most frequently reported unsolicited non-serious AE. There were no notable differences in the overall frequency rates of solicited reactions between participants aged ≤ 23 months and those aged ≥ 24 months.

The overall safety profile of QIV observed in this study is at least generally consistent with the findings of three large-scale, phase III randomized, controlled, global clinical trials of QIVs (VaxigripTetra [Sanofi], Influvac Tetra [Abbott], and Fluarix Quadrivalent [GlaxoSmithKline], respectively) in children aged 6–35 months [12,13,14], as well those of a smaller, single-arm bridging study of another QIV (PT Bio Farma) in Indonesia that included this age group [15]. Notably, in the three global clinical studies, the overall safety profile of QIVs was shown to be comparable with that of the non-influenza control vaccines [12, 14], and aside from a slightly higher frequency of injection site reactions, with that of placebo also [13]. Our safety findings are also consistent with those of a wide range of clinical studies of QIV (VaxigripTetra) across age groups > 3 years, which have demonstrated favorable tolerability and safety, with reported safety events generally of mild or moderate severity [8, 16,17,18]. Our study further supports the overall safety profile of QIV (VaxigripTetra) observed in a number of enhanced safety surveillance studies conducted in routine practice in Europe (which included a small proportion of participants aged 6–35 months) [19,20,21,22,23].

Limitations of our study included the sample size chosen; this lacked sufficient numbers of participants to detect rare events. In addition, inherent to observational post-marketing surveillance study, there was no comparator or control agent, and as such the background rate of the events reported is unknown in the childhood population assessed. However, the advantage of this design is the generation of real-world data on the safety of QIV used in routine clinical practice.

Conclusion

Our post-marketing safety surveillance study confirms that QIV is well tolerated in children aged 6–35 months in routine clinical practice in South Korea and has an acceptable safety profile with no safety concerns.