Enhanced passive safety surveillance of standard-dose and high-dose influenza vaccines in Finland and Germany 2023–24 season

ABSTRACT

Enhanced Passive Safety Surveillance was used to detect safety signals before the peak period of immunization with quadrivalent inactivated influenza vaccines (IIV4) in Finland (standard dose [SD]) and Germany (high dose [HD]) in the 2023–24 season. The primary objective was to evaluate adverse drug reactions (ADRs) occurring ≤7 days following IIV4 vaccination. Enrolled participants were vaccinated in routine clinical care settings and encouraged to report ADRs. Exposure data and ADR reports were collected in a near real-time manner using an electronic system. Vaccinee reporting rate (RR) with 95% confidence interval (CI) was calculated as the number of vaccinees reporting ≥ 1 ADR divided by total number of vaccinees. In Finland for SD-IIV4, among 1,003 vaccinees aged ≥ 6 months, 81 reported a total of 192 suspected ADRs occurring ≤ 7 days following vaccination (vaccinee RR 8.08%; 95% CI 6.46, 9.94). In Germany for HD-IIV4, among 1,075 vaccinees aged ≥ 60 years, 15 reported 46 ADRs that occurred in ≤ 7 days of vaccination (vaccinee RR 1.40%; 95% CI 0.78, 2.29). No safety signal was detected during this surveillance. The 2023–24 season surveillance did not suggest any clinically significant changes in safety profile compared with previously reported safety data for SD-IIV4 and HD-IIV4.

Introduction

Approximately 3 to 5 million cases of severe infection and 290,000 to 650,000 deaths worldwide are attributed to seasonal influenza epidemics annually.¹ Among hospitalizations due to lower respiratory tract infections, 8.5% are estimated to be caused by influenza viruses.² Up to 50 million symptomatic influenza infection cases occur in Europe, resulting in 15,000 to 70,000 influenza-related deaths among European citizens annually.³ Annual seasonal influenza vaccination continues to be the mainstay of influenza prevention.⁴

Seasonal vaccines are annually reformulated following World Health Organization (WHO) recommendations to match the predominant circulating strains of the influenza virus evolving through antigenic drift.⁵ For each seasonal influenza vaccine licensed and used in the European Union, Marketing Authorization Holders are required to conduct annual enhanced safety surveillance to identify significant variations between the known or anticipated frequency and/or severity of reactogenicity of the prior influenza vaccine formulation compared to the formulation of the current season.^6,7 This surveillance can involve active collection of data on adverse events following immunization or collection of adverse events via spontaneous reporting (passive surveillance).⁶ The enhanced passive safety surveillance (EPSS) encourages vaccinees and healthcare professionals (HCPs) to report adverse events promptly, through the dissemination of information on reporting procedures and patient education.^6,8

Quadrivalent influenza vaccines containing antigens of two A and two B influenza virus strains were recommended for season 2023–24 in Europe.⁵ The standard-dose (SD)-quadrivalent inactivated split-virion influenza vaccine (IIV4) (Vaxigrip Tetra®, Sanofi) is indicated for children aged 6 months or older and adults, including pregnant women, and was first approved in Europe in 2016. In Finland, SD-IIV4 is provided via the national vaccination program for children aged ≥6 months to <7 years, adults aged ≥65 years, pregnant women, new military recruits, special risk groups, and selected professional groups.⁹ The high-dose (HD)-IIV4 (Efluelda®, Sanofi) was available in Germany in 2021 with a preferential recommendation over other influenza vaccines in adults aged ≥60 years.¹⁰ HD-IIV4 contains 60 mcg of hemagglutinin antigen (HA) per strain (in contrast of 15 mcg in SD-IIV4) and has superior clinical efficacy against laboratory-confirmed influenza infections and increased protection against influenza complications compared to SD-IIV4.^11,12 Prior EPSS conducted in Finland and Germany with SD-IIV4 and HD-IIV4, respectively, in the past seasons did not report any clinically significant change in safety beyond what is known or expected of these vaccines.^8,13 In the Northern Hemisphere (NH) 2023–24 influenza season, an EPSS was performed in the same countries to detect any variation in the reactogenicity compared to previous experience with SD-IIV4 and HD-IIV4. The primary objective was to estimate the vaccinee reporting rate (RR) of suspected ADRs within 7 days following routine vaccination with SD-IIV4 and HD-IIV4. The 7-day period following vaccination was chosen as the time window for the main analysis because most immediate and short-term adverse reactions to influenza vaccines typically occur within the first few days after vaccination.¹⁴ The secondary objective was to compare vaccinee RRs of suspected ADRs with rates observed in prior EPSS (2021–22 and 2022–23 seasons) and the summaries of product characteristics (SmPC) for SD-IIV4 and HD-IIV4.

Methods

Study setting and population

This EPSS evaluated individuals receiving SD-IIV4 in Finland and HD-IIV4 in Germany during the NH 2023–24 influenza season. The decision to vaccinate was entirely at the discretion of the HCPs in the vaccination sites, independent of the surveillance implementation. The EPSS began with the start of seasonal influenza vaccination at participating sites in Finland and Germany in autumn 2023. The enrollment was planned to continue for 4 to 6 weeks until the sample size target of 1,000 vaccinees was reached in each country. This sample size was designed to detect ADRs considered common (rate of ≥ 1%), aligning with the European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) recommendations.⁶ This approach focuses on identifying any notable increases in the frequency and/or severity of common ADRs rather than detecting rare adverse events. This study was carried out in routine clinical care settings for participants aged ≥6 months in Finland and ≥60 years in Germany.

The study was conducted in accordance with the Declaration of Helsinki, Good Epidemiological Practice, and the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance. In Finland, no ethics committee submission was required for conducting this study. In Germany, approval from the Ethics Committee at the Ludwig Maximilian University of Munich was obtained prior to the initiation of the study. Informed consent was not required for participation as this study relied completely on routine pharmacovigilance, i.e. voluntary spontaneous reporting.

Study vaccines

In Finland, participants received SD-IIV4 (Vaxigrip Tetra®) containing 15 μg HA per influenza strain. In Germany, participants received HD-IIV4 (Efluelda®) containing 60 μg HA per influenza strain. The vaccines were administered intramuscularly and contained the WHO recommended viral strains for egg-based vaccines for the NH 2023–24 influenza season: A/Victoria/4897/2022 (H1N1) pdm09-like virus, A/Darwin/9/2021 (H3N2)-like virus, B/Austria/1359417/2021 (B/Victoria lineage)-like virus, and B/Phuket/3073/2013 (B/Yamagata lineage)-like virus.⁵

Study conduct and data collection

Before the vaccination campaigns and enrollment of vaccinees, the HCPs from the participating sites received remote training on the study procedures. They were also instructed to inform the vaccinees or their legally accepted representative (LAR) about the importance of reporting any ADRs. In addition, vaccination cards (VC) were distributed to the sites (Figure 1). The VCs are presented in the Supplemental Materials 1 and 2.

Figure 1.

Pictorial schema of study conduct and data collection.

ADR, adverse drug reaction; EDC, electronic data capture; HCP, health care professional; LAR, legally accepted representative; PV, pharmacovigilance.

At the vaccination sites, during enrollment, VCs were handed to each vaccinee/LAR. The VCs contained name of the vaccine, date of vaccination, batch number, age group (only for administration of SD-IIV4), and a VC number, which was used to link the vaccine administration to a potential ADR report. COVID-19 vaccine co-administration could occur with recipients of both SD-IIV4 and HD-IIV4 vaccines; however, this was only anticipated in Germany, where the probability of co-administration was expected to be high due to the target population for HD-IIV4 (individuals aged ≥60 years). Therefore, in Germany, the VC was also used to record COVID-19 vaccine co-administration if both vaccines were given at the same day. Using a copy of the VC, the HCPs entered the exposure data on the electronic data capture (EDC) system.

The HCPs explained the importance of reporting ADRs and encouraged the vaccinees and their LARs to report any ADR experienced post vaccination, especially those occurring within the first 7 days. The time window for ADR reporting spanned two weeks after the last VC. As a result, individuals vaccinated prior to the last VC distributed had over 2 weeks to report any ADR. The VC contained information for reporting ADRs via the EDC system or by telephone to the local Sanofi Pharmacovigilance (PV) affiliates. Each new ADR report in the electronic system triggered an automatic notification to the Sanofi PV system, allowing for rapid processing of any safety concerns. The EDC system provided structured ADR forms enabling the collection of any ADRs, but with dedicated fields for the following adverse events of interest (AEIs) as recommended by PRAC: fever (≥38°C), nausea, vomiting, malaise, headache, decreased appetite, myalgia, arthralgia, irritability (vaccinees <5 years), crying (vaccinees <5 years), injection site reactions (e.g., pain, erythema, swelling), and events indicative of allergic and hypersensitivity reactions, including rash and ocular symptoms.⁶ Verbatim ADRs were entered in the PV database and coded with Medical Dictionary for Regulatory Activities (MedDRA) terminology (version 26.1) and processed according to routine PV processes. The ADRs were described based on the seriousness and maximum intensity grade experienced by a vaccinee (i.e., mild, moderate, or severe). The ADRs were classified as AEI, identified/potential risks as defined in the risk management plans (RMP) of the products, and Other ADRs. The ADR forms are presented in the Supplemental Materials 3 and 4.

Statistical analysis

Data were summarized cumulatively by ADRs occurring ≤7 days post vaccination and during the entire data collection period. Analysis was stratified by age groups (≥6 months to <6 years, ≥6 to <13 years, ≥13 to <18 years, ≥18 to <65 years, and ≥65 years) for the SD-IIV4 in Finland. Vaccinee RR with associated two-sided 95% confidence intervals (CIs) (Clopper – Pearson method) was calculated using the number of vaccinees who reported at least one suspected ADR (numerator) and the total number of vaccinees (denominator).

Comparison of the reported frequencies with previous NH influenza seasons

The vaccinee RRs of season 2023–24 were compared with rates described in both 2022–23 and 2021–22 seasons.^8,13 If the point estimate of the RR in the 2023–24 season exceeded the upper limit of the 95% CI from previous season (2022–23 or 2021–22), the RR was considered above the previous season; otherwise, the rates were considered similar. ADRs not reported in the previous two seasons had their rates referenced against the SmPC.^15,16 The vaccinee RR in the EPSS was considered higher than the SmPC if the point estimate of the rate was above the upper limit of the frequency range in the SmPC.

Results

In Finland, one participating site included 1,003 participants over 6 months of age who received SD-IIV4. The distribution of vaccinees by age group was as following: 202 (20.1%) aged ≥6 months to <6 years, 38 (3.8%) aged ≥6 to <13 years, 20 (2.0%) aged ≥13 to <18 years, 346 (34.5%) aged ≥18 to <65 years, and 397 (39.6%) aged ≥65 years. The first VC was distributed on 02-Nov-2023 and the last on 01-Dec-2023; safety data collection took place up to 15-Dec-2023 (2 weeks after the last VC was distributed). Ten participating sites in Germany enrolled 1,075 participants ≥60 years of age who were vaccinated with HD-IIV4. On the same day of vaccination with HD-IIV4, 204 vaccinees (19.0%) received COVID-19 vaccine. The first and last VC were distributed on 02-Oct-2023 and 27-Oct-2023, respectively; safety data collection took place up to 10-Nov-2023 (2 weeks after the last VC was distributed).

Safety of SD-IIV4

Among 1,003 vaccinees, 83 reported a total of 211 suspected ADRs following vaccination with SD-IIV4. The time to ADR onset was known for 192 ADRs and all of them occurred within the first 7 days following vaccination and were reported by 81 vaccinees (vaccinee RR 8.08%; 95% CI 6.46, 9.94). Among these 192 events, 150 were AEIs reported by 75 vaccinees (vaccinee RR 7.48%; 95% CI 5.93, 9.28) and 42 were Other ADRs reported by 29 vaccinees (vaccinee RR 2.89%; 95% CI 1.94, 4.13). No events classified as an identified or potential risk according to the RMP were reported, nor were any serious ADRs reported. Within the first 7 days, most of the ADRs reported were of mild (vaccinee RR 5.88%; 95% CI 4.51, 7.52) and moderate intensity (vaccinee RR 3.09%; 95% CI 2.11, 4.36) (Table 1).

Table 1.

Summary of reported ADRs for SD-IIV4 in Finland and HD-IIV4 in Germany.

	SD-IIV4 in Finland (N = 1,003)			HD-IIV4 in Germany (N = 1,075)
	Number of vaccinees	Number ofADRs	Vaccinee RR(95% CI)	Number of vaccinees	Number ofADRs	Vaccinee RR(95% CI)
ADR ≤7 days of vaccination	81	192a	8.08 (6.46, 9.94)	15	46b	1.40 (0.78, 2.29)
AEI	75	150c	7.48 (5.93, 9.28)	14	29d	1.30 (0.71, 2.18)
Other ADR	29	42	2.89 (1.94, 4.13)	7	17	0.65 (0.26, 1.3)
ADR by intensity
Mild	59	97	5.88 (4.51, 7.52)	5	7	0.47 (0.15, 1.08)
Moderate	31	56	3.09 (2.11, 4.36)	6	20	0.56 (0.21, 1.21)
Severe	4	5	0.40 (0.11, 1.02)	3	5	0.28 (0.06, 0.81)
Unknown	8	26	0.80 (0.34, 1.57)	5	14	0.47 (0.15, 1.08)
Serious ADR	0	0	0.00 (0.00, 0.37)	1	6	0.09 (0.00, 0.52)
ADR during the entire data collection period	83	211	8.28 (6.64, 10.16)	16	52	1.49 (0.85, 2.41)
AEI	77	161	7.68 (6.11, 9.50)	15	33	1.40 (0.78, 2.29)
Other ADR	32	50	3.19 (2.19, 4.47)	7	19	0.65 (0.26, 1.3)
ADR by intensity
Mild	63	101	6.28 (4.86, 7.97)	5	7	0.47 (0.15, 1.08)
Moderate	31	56	3.09 (2.11, 4.36)	6	20	0.56 (0.21, 1.21)
Severe	4	5	0.40 (0.11, 1.02)	3	5	0.28 (0.06, 0.81)
Unknown	10	41	1.00 (0.48, 1.83)	6	20	0.56 (0.21, 1.21)
Serious ADR	0	0	0.00 (0.00, 0.37)	1	6	0.09 (0.00, 0.52)

ADR, adverse drug reaction; AEI, adverse events of interest (as defined by Pharmacovigilance Risk Assessment Committee); CI, confidence interval; HD, high dose; IIV4, quadrivalent inactivated split-virion influenza vaccine; N, number of vaccinees; RR, reporting rate; SD, standard dose.

^aTime to onset was known for 192 ADRs (91.0%, 192/211).

^bTime to onset was known for 48 ADRs (92.3%, 48/52).

^cTime to onset was known for 150 AEIs (93.2%, 150/161).

^dTime to onset was known for 30 AEIs (90.9%, 30/33).

Among events occurring within the first 7 days post-vaccination, vaccinees reported more frequently AEIs of injection site reaction (vaccinee RR 5.08%; 95% CI 3.81, 6.63), including pain, swelling, and erythema at the vaccination site; myalgia (vaccinee RR 1.89%; 95% CI 1.14, 2.94); and malaise (vaccinee RR 1.60%; 95% CI 0.91, 2.58) (Table 2). Among Other ADRs, vaccinees frequently reported diarrhea (vaccinee RR 0.60%; 95% CI 0.22, 1.30) (Supplementary Table S1).

Table 2.

Reported AEIs within 7 days post-vaccination for SD-IIV4 in Finland and HD-IIV4 in Germany.

	SD-IIV4 in Finland (N = 1,003)			HD-IIV4 in Germany (N = 1,075)
	Number of vaccinees	Number of ADRs	Vaccinee RR (95% CI)	Number of vaccinees	Number of ADRs	Vaccinee RR (95% CI)
Arthralgia	3	3	0.30 (0.06, 0.87)	1	1	0.09 (0.00, 0.52)
Crying*	7	7	0.70 (0.28, 1.43)	–	–	–
Decreased appetite	5	5	0.50 (0.16, 1.16)	0	0	0.00 (0.00, 0.34)
Events indicative of allergic and hypersensitivity reactions**	2	2	0.20 (0.02, 0.72)	1	1	0.09 (0.00, 0.52)
Fever	4	4	0.40 (0.11, 1.02)	2	2	0.19 (0.02, 0.67)
Headache	16	16	1.60 (0.91, 2.58)	4	4	0.37 (0.10, 0.95)
Injection site reaction	51	61	5.08 (3.81, 6.63)	10	15	0.93 (0.45, 1.70)
Irritability*	5	5	0.50 (0.16, 1.16)	–	–	–
Malaise	16	21	1.60 (0.91, 2.58)	0	0	0.00 (0.00, 0.34)
Myalgia	19	19	1.89 (1.14, 2.94)	2	2	0.19 (0.02, 0.67)
Nausea	5	5	0.50 (0.16, 1.16)	3	3	0.28 (0.06, 0.81)
Vomiting	2	2	0.20 (0.02, 0.72)	0	0	0.00 (0.00, 0.34)

AEI, adverse events of interest (as defined by Pharmacovigilance Risk Assessment Committee); CI, confidence interval; HD, high dose; IIV4, quadrivalent inactivated split-virion influenza vaccine; N, number of vaccinees; SD, standard dose; RR, reporting rate.

*Crying and irritability are defined as adverse event of interest only for children aged under 5 years-old.

**Including rash and ocular symptoms.

Suspected ADRs were reported across all age groups. Among children aged ≥6 months to <6 years, out of 23 AEIs occurring within 7 days after vaccination, the most frequent were crying (vaccinee RR 3.47%; 95% CI 1.40, 7.01) and irritability (vaccinee RR 2.48%; 95% CI 0.81, 5.68). Vaccinees aged ≥65 years presented the lowest vaccinee RR for all ADRs and AEIs compared with the other age groups (Table 3).

Table 3.

Reported ADRs and AEIs within 7 days post-vaccination by age group for SD-IIV4 in Finland.

	Number of vaccinees	Number of ADRs	Vaccinee RR (95% CI)
≥6 months to <6 years (N = 202)
ADR	14	32	6.93 (3.84, 11.36)
AEI	12	23	5.94 (3.11, 10.15)
Crying*	7	7	3.47 (1.40, 7.01)
Decreased appetite	2	2	0.99 (0.12, 3.53)
Events indicative of allergic and hypersensitivity reactions**	1	1	0.50 (0.01, 2.73)
Injection site reaction	3	4	1.49 (0.31, 4.28)
Irritability*	5	5	2.48 (0.81, 5.68)
Malaise	2	2	0.99 (0.12, 3.53)
Vomiting	2	2	0.99 (0.12, 3.53)
≥6 to <13 years (N = 38)
ADR	4	11	10.53 (2.94, 24.80)
AEI	4	10	10.53 (2.94, 24.80)
Events indicative of allergic and hypersensitivity reactions**	1	1	2.63 (0.07, 13.81)
Fever	1	1	2.63 (0.07, 13.81)
Headache	1	1	2.63 (0.07, 13.81)
Injection site reaction	2	4	5.26 (0.64, 17.75)
Malaise	1	1	2.63 (0.07, 13.81)
Myalgia	2	2	5.26 (0.64, 17.75)
≥13 to <18 years (N = 20)
ADR	4	13	20.00 (5.73, 43.66)
AEI	4	13	20.00 (5.73, 43.66)
Decreased appetite	1	1	5.00 (0.13, 24.87)
Headache	3	3	15.00 (3.21, 37.89)
Injection site reaction	4	4	20.00 (5.73, 43.66)
Malaise	2	4	10.00 (1.23, 31.70)
Nausea	1	1	5.00 (0.13, 24.87)
≥18 to <65 years (N = 346)
ADR	40	90	11.56 (8.39, 15.41)
AEI	39	71	11.27 (8.14, 15.09)
Arthralgia	2	2	0.58 (0.07, 2.07)
Decreased appetite	1	1	0.29 (0.01, 1.60)
Fever	1	1	0.29 (0.01, 1.60)
Headache	6	6	1.73 (0.64, 3.74)
Injection site reaction	34	41	9.83 (6.90, 13.46)
Malaise	6	7	1.73 (0.64, 3.74)
Myalgia	11	11	3.18 (1.60, 5.62)
Nausea	2	2	0.58 (0.07, 2.07)
≥65 years (N = 397)
ADR	19	46	4.79 (2.91, 7.37)
AEI	16	33	4.03 (2.32, 6.46)
Arthralgia	1	1	0.25 (0.01, 1.40)
Decreased appetite	1	1	0.25 (0.01, 1.40)
Fever	2	2	0.50 (0.06, 1.81)
Headache	6	6	1.51 (0.56, 3.26)
Injection site reaction	8	8	2.02 (0.87, 3.93)
Malaise	5	7	1.26 (0.41, 2.91)
Myalgia	6	6	1.51 (0.56, 3.26)
Nausea	2	2	0.50 (0.06, 1.81)

ADR, adverse drug reaction; AEI, adverse events of interest (as defined by Pharmacovigilance Risk Assessment Committee); CI, confidence interval; N, number of vaccinees; IIV4, quadrivalent inactivated split-virion influenza vaccine; RR, reporting rate; SD, standard dose.

*Crying and irritability are defined as adverse event of interest only for children aged under 5 years old.

**Including rash and ocular symptoms.

The vaccinee RR for the present season (2023–24) was greater than that of the seasons 2022–23 (4.80%; 95% CI 3.56, 6.31) and 2021–22 (4.90%; 95% CI 3.65, 6.43) for ADRs with time to onset within 7 days following vaccination. For the entire data collection period, similar trend was observed (2022/23 vaccinee RR 5.09% [95% CI 3.82, 6.64]; 2021/22 vaccinee RR 5.10% [95% CI 3.82, 6.65]). In the previous two seasons, there were no or very few vaccinees in the age groups under 18 years old, precluding comparisons with the current season. Vaccinees aged ≥ 18 to <65 years presented higher vaccinee RRs in the current season compared with seasons 2022–23 and 2021–22. For the elderly group, the vaccinee RRs for all suspected ADRs were within the rates reported in the seasons 2022–23 and 2021–22.

The following events were not reported in the prior two seasons. The vaccinee RRs for vaccination site discomfort (0.10%, 95% CI 0.00, 0.55) and asthenia (0.30%, 95% CI 0.06, 0.87) were higher than the frequency in the SmPC (rare: ≥0.01% to < 0.10%); however, the 95% CIs overlapped with the frequency range. Crying, irritability, and vomiting were reported for children aged ≥6 months to <6 years with vaccinee RRs lower than the frequency range in the SmPC (vaccinee RRs: ≤3.47% vs very common: ≥10% for all three events). Contusion was reported with a vaccinee RR (0.10%, 95% CI 0.00, 0.55) within the expected frequency according to the SmPC (uncommon: ≥0.1% to < 1%).¹⁵ The following events were neither reported in the previous two seasons nor listed in the SmPC and accounted for a total of 28 ADRs: vaccination site mass, maternal exposure during breastfeeding, exposure during pregnancy, heat stroke, feces discolored, lip blister; herpes virus infection; cough, dysphonia, nasal congestion, productive cough, feeling hot, discomfort, sleep disorder, tension; muscular weakness, dysgeusia, hyperesthesia, presyncope.

Safety of HD-IIV4

Among the 1,075 vaccinees, 16 reported a total of 52 suspected ADRs following vaccination with HD-IIV4. A total of 15 vaccinees reported 46 ADRs occurring within the first 7 days of vaccination (time to ADR onset was unknown for 4 ADRs), yielding a vaccinee RR of 1.40% (95% CI 0.78, 2.29). Among all ADRs which occurred within the first 7 days, 29 were AEIs reported by 14 vaccinees (vaccinee RR 1.30%; 95% CI 0.71, 2.18) and 17 were Other ADRs reported by 7 vaccinees (vaccinee RR 0.65%; 95% CI 0.26, 1.34). There were no ADRs reported that qualified as an identified/potential risk as defined in the RMP. For the time frame of 7 days, three vaccinees reported five severe ADRs (vaccinee RR 0.28%; 95% CI 0.06, 0.81) and one vaccinee reported six serious ADRs (vaccinee RR 0.09%; 95% CI 0.00, 0.52) (Table 1). These 6 serious ADRs comprised 2 AEIs (headache and body temperature increased) and 4 Other ADRs (chills, gait disturbance, tendon pain, and pain in extremity).

The three most frequently reported AEIs occurring in the 7-day period post-vaccination were injection site reaction (vaccinee RR 0.93%; 95% CI 0.45, 1.70), including pain, swelling, and erythema at the vaccination site; headache (vaccinee RR 0.37%; 95% CI 0.10, 0.95); and nausea (vaccinee RR 0.28%; 95% CI 0.06, 0.81) (Table 2). In this same time frame for Other ADRs, the highest reporting rate was for chills (vaccinee RR 0.28%; 95% CI 0.06, 0.81) (Supplementary Table S1).

For the ADRs occurring within 7 days post-vaccination, the vaccinee RR was higher in season 2023–24 than in the season 2022–23 (0.58%; 95% CI 0.21, 1.25) and within the rate reported in the season 2021–22 (1.88%; 95% CI 1.10, 3.00). For the overall period of ADR onset, the vaccinee RR of the current season (2023–24) was within the rates reported in the seasons 2022–23 (0.96%; 95% CI 0.46, 1.76) and 2021–22 (2.10%; 95% CI 1.27, 3.27).

Events of dizziness, rhinorrhea, cough, and dyspepsia were not reported in the previous two seasons (2022–23 and 2021–22). The vaccinee RR for dizziness (0.19%; 95% CI 0.02, 0.67) was higher than the frequency in the SmPC (rare: ≥0.01% to < 0.10%), although the 95% CIs overlapped with the frequency range. The vaccinee RR for rhinorrhea (0.09%; 95% CI 0.00, 0.52) was within the frequency range in the SmPC (rare: ≥0.01% to < 0.10%). For cough and dyspepsia, the rates were lower than the frequencies listed in the SmPC (vaccinee RR: 0.09% [95% CI: 0.00, 0.52] vs uncommon: ≥0.10% to <1.00% for both events).¹⁶ The events of periorbital swelling, gait disturbance, sinonasal obstruction, migraine, loss of personal independence in daily activities, and tendon pain were each reported by one vaccinee during the season 2023–24; these events were neither reported in the previous two seasons nor listed in the SmPC.

Discussion

In this EPSS conducted during the 2023–24 influenza season in Finland for SD-IIV4 and Germany for HD-IIV4 with vaccinees aged ≥6 months and ≥60 years, respectively, most of reported ADRs occurred within the first 7 days following vaccination. In this time frame, the vaccinee RRs were 8.08% (95% CI 6.46, 9.94) for SD-IIV4 and 1.40% (95% CI 0.78, 2.29) for HD-IIV4. In both countries, the most frequent reported ADR was injection site reaction, mainly vaccination site pain, and no safety signal was detected.

In Finland, since season 2018–19, the safety profile of SD-IIV4 has been confirmed through the conduct of EPSS, especially in adults given that previous EPSS enrolled predominantly 18 to 64-year-old vaccinees.^8,13 In the current season, the EPSS successfully improved representation of infants (20.1% ≥6 months to <6 years) and elderlies (39.6% ≥65 years), which contributed to demonstrate the safety evidence along different age groups covered by the indication of SD-IIV4. In the current season, the vaccinee RRs for ADRs occurring anytime or within 7 days after vaccination were higher in comparison to seasons 2021–22 and 2022–23.^8,13 This increase could be attributed to a few factors. Firstly, a higher presence of pediatric population in the current season as the selected site successfully enrolled more vaccinees within this specific age group. Consequently, in the current season, events only reported in children (i.e., crying and irritability) contributed to a higher count of ADRs when all age groups were combined. Secondly, the high number of reports of vaccination site pain in the current season likely contributed to an elevated aggregated vaccinee RR for all ADRs; though higher than the previous seasons, the rate of vaccination site pain (5.28%; 95% CI 3.98, 6.86) is lower than the frequency range described in the SmPC (very common ≥ 10%). Finally, the participating site recruited a high number of HCPs aged ≥18 to <65 years who received their vaccinations through occupational healthcare and were presumably more prone to report an ADR that they had experienced, leading to an increased RR in this age group during this season. Particularly for vaccinees aged ≥65 years, the rates reported in the current season were similar to the rates reported in the seasons 2023–24 and 2021–22. Of note, elderlies presented lower vaccinee RR compared with other age groups, which was also observed in a safety surveillance of influenza vaccines in Australia.¹⁷

In Germany, the Standing Committee on Vaccination (STIKO) has recommended HD-IIV4 since 2021–22 season over SD formulations to adults aged ≥60 years.^a,¹⁰ In the seasons 2021–22 throughout 2023–24, the EPSS has demonstrated favorable safety profile of HD-IIV4 in this population and consistent with the product information.^8,13 Although the vaccinee RR for ADRs that occurred within 7 days after vaccination was higher in the current season than in the 2022–23 season, the 95% CIs overlapped and, for ADRs at any time to onset, the rates in these two seasons were similar. Notably, in the EPSS 2022–23 season, the estimated rate of events occurring within the first 7 days was affected by the fact that half of the reports had an unknown time to onset.⁸

The goal of the EPSS to identify potential risks associated with influenza vaccination prior to the peak period of mass immunization was guaranteed mainly by the use of the EDC system to register enrolled vaccinees and to capture ADR reports, which allowed for near-real-time monitoring of both vaccine exposure and safety data. In addition, this approach enhanced accuracy and completeness of ADR reports and facilitated data management.

The data collected for all vaccinees were limited to date of vaccination, batch number, and age group (only for administration of SD-IIV4). Additional information (e.g., medical history, concomitant treatment) could be available for vaccinees that reported ADRs, depending on what was indicated in the ADR form. While the importance of demographics and social determinants of health (SDOH) in influencing health outcomes and reporting rates is well recognized, this EPSS did not include assessment of other demographics or SDOH. Furthermore, this EPSS did not collect data on participants’ prior influenza vaccination history, precluding analysis of vaccinee RR based on previous vaccine exposure. It’s worth noting that some individuals may experience hypersensitivity reactions following influenza vaccination in subsequent seasons.

All ADRs in this EPSS were self-reported by vaccinees and were not medically confirmed. Although most reports detailed uncomplicated ADRs, searching additional details for every ADR would have been challenging. Due to the spontaneous nature of ADR reporting, two potential biases were present: (1) underreporting, where only a fraction of the total ADRs are reported, excluding vaccinees who experienced ADRs but did not report them; and (2) differential reporting, where serious ADRs and those with shorter onset times are more likely to be reported than minor ADRs or those with longer onset times. Another limitation is that this study may have been influenced by digital exclusion, particularly among older participants.¹⁸ While the majority of participants in both countries used the electronic reporting system, individuals less comfortable with digital technology may have been underrepresented in the ADR reporting.

In Germany, 19.0% of the vaccinees received a COVID-19 vaccine on the same day. Among the vaccinees that reported at least one ADR, 31.3% (5/16) were co-administered with COVID-19 vaccine on the same day and others may have received COVID-19 vaccine either prior or post-influenza vaccination. In Finland, co-administration of influenza and COVID-19 vaccines cannot be ruled out either. Consequently, determining the causality of symptoms could be confounded in vaccinees when administration of multiple vaccines occurred.

Conclusions

No significant patterns by type, frequency, or severity of suspected ADRs were reported in the EPSS NH 2023–24 for vaccination with either SD-IIV4 or HD-IIV4 in Finland and Germany, respectively. The results of this EPSS were consistent with what is known or expected for the SD-IIV4 and HD-IIV4.

Biography

Marina Amaral de Avila Machado is a pharmacoepidemiologist at Sanofi and leads the development of post-authorization safety studies for vaccines and conducts pharmacovigilance activities. Marina holds a bachelor’s degree in Pharmacy and a PhD in Epidemiology. With 18 years of experience across academia, the public, and private sectors, she has authored 20 peer-reviewed publications and made significant contributions to comparative safety and effectiveness research of drugs and vaccines, drug utilization research, health technology assessment, and public health.

Funding Statement

This study was funded by Sanofi.

Disclosure statement

MAAM, SG, AG, PV, and RMB are employees of Sanofi and may hold shares and/or stock options in the company. JS received honoraria for conferences, presentations, speaker bureaus and educations events from GSK, MSD, Sanofi, Pfizer, BioNTech, Moderna, Novavax, Takeda, Bavarian Nordic, Viatris, Seqirus, Novartis, Janssen, AstraZeneca, KVB, LAGI, BLÄK, BHÄV. AK and HV declare no competing interests.

Author contributions

MAAM, SG, AG, PV, and RMB contributed to the concept or design of the study. AK, HV, and JS contributed to the data acquisition of the study. All authors contributed to the data analysis or interpretation and drafting and critically revising the manuscript. All authors gave final approval for publication and are accountable for the accuracy and integrity of the data presented.

Data availability statement

The datasets generated and/or analyzed during the current study, including the raw data, are not publicly available in order to safeguard the privacy of participants and the confidentiality and protection of their data, as well as protect commercially sensitive information. Qualified researchers may request access to individual participant-level data and related study documents, including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan and dataset specifications. Individual participant-level data would be anonymized, and study documents would be redacted to protect the privacy of study participants. Further details on Sanofi’s data sharing criteria, eligible studies and process for requesting access can be found at https://www.vivli.org/, and summarized data can be made available on reasonable request.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/21645515.2025.2475616