Enhanced passive safety surveillance of high-dose and standard-dose quadrivalent inactivated split-virion influenza vaccines in Germany and Finland during the 2022/23 influenza season

ABSTRACT

Enhanced Passive Safety Surveillance (EPSS) was conducted for quadrivalent inactivated split-virion influenza vaccines (IIV4) in Germany (high dose [HD]) and Finland (standard dose [SD]) for the northern hemisphere (NH) 2022/23 influenza season. The primary objective was to assess adverse events following immunization (AEFI) occurring ≤7 days post-vaccination. In each country, the EPSS was conducted at the beginning of the NH influenza season. Exposure information was documented using vaccination cards (VC), and AEFI were reported via an electronic data collection system or telephone. AEFI were assessed by seriousness and age group (Finland only). The vaccinee reporting rate (RR) was calculated as the number of vaccinees reporting ≥ 1 AEFI divided by the total vaccinees. In Germany, among 1041 vaccinees, there were 31 AEFI (ten vaccinees) during follow-up, including one serious AEFI. Of 16 AEFI (six vaccinees) with reported time of onset, 15 occurred ≤7 days post-vaccination (RR 0.58%, 95% confidence interval [CI] 0.21, 1.25), which was lower than the 2021/22 season (RR 1.88%, 95% CI: 1.10, 3.00). In Finland, among 1001 vaccinees, there were 142 AEFI (51 vaccinees) during follow-up, none of which were serious. Of 133 AEFI (48 vaccinees) with time of onset reported, all occurred ≤7 days post-vaccination (RR 4.80%, 95% CI: 3.56, 6.31), which was similar to the 2021/22 season (RR 4.90%, 95% CI: 3.65, 6.43). The EPSS for HD-IIV4 and for SD-IIV4 in the 2022/23 influenza season did not suggest any clinically relevant changes in safety beyond what is known/expected for IIV4s.

KEYWORDS:

• Seasonal influenza
• influenza vaccine
• IIV4
• Efluelda
• Vaxigrip Tetra
• quadrivalent split-virion inactivated influenza vaccine

Introduction

The European Medicines Agency (EMA) requires manufacturers of seasonal influenza vaccines to conduct annual safety surveillance to detect clinically significant changes in the frequency and/or severity of reactogenicity versus what is known or expected with the previous vaccine composition.^1–6 Compared with active surveillance, involving the collection of data on adverse events following immunization (AEFI) as a continuous preorganized process instigated by the manufacturer, enhanced passive safety surveillance (EPSS) encourages vaccinees and healthcare professionals (HCPs) to report adverse events as and when they occur, through the dissemination of information on reporting, a structured electronic reporting system and patient education. EPSS enables spontaneous reporting of AEFI following increasing vaccine exposure, and is performed in a routine clinical setting to identify potential clinically relevant safety concerns before the peak immunization period each year.¹

During recent years in Europe, influenza vaccine manufacturers have conducted EPSS studies using electronic data collection (EDC) systems, using a web-based portal and a back-up number for a call-center.^3–4,6–8 Some studies have also used e-mail reporting or postal reporting using prepaid envelopes. Based on EPSS studies of quadrivalent inactivated influenza vaccine (IIV4) over several seasons in Finland, web-based/call center reporting and pre-paid envelopes/call center reporting both captured more events than e-mail reporting.^4,6,7 In an EPSS study of IIV4 in Germany and Spain in 2021/22, web-based/call center reporting captured fewer events than in the previous season using paper-based reporting.⁸ Differences in reporting rates between seasons and data collection methods are due to various factors; however, enabling vaccinees to report directly into a web-based system appears to improve data quality and reporting impetus compared with traditional safety surveillance where AEFI are reported to and recorded by HCPs.^3–4,6–8

Following the impact of the COVID-19 pandemic, the 2021/22 influenza season was unprecedented, with later onset and shorter duration compared with influenza seasons since the 2009 influenza pandemic.⁹ The COVID-19 restriction measures implemented across Europe may have also resulted in low-level influenza circulation, causing a resurgence in influenza when the restrictions were lifted. As such, the 2022/23 incidence of influenza almost returned to pre-COVID-19 pandemic levels, with more than a four-fold increase in positive sentinel specimens.¹⁰ Despite both the 2021/22 and 2022/23 seasons being dominated by type A influenza (H3N2), the proportion of type B increased in 2022/23 (from 1% to 33%), albeit maintaining a low presence of B/Yamagata subtype. Therefore, comparisons between seasons are challenging due to variations in the circulating viruses and timing of influenza infections.^9,10

In Germany, high-dose (HD)-IIV4 vaccine (Efluelda®, Sanofi) was introduced in 2021 with a preferential recommendation over other influenza vaccines in adults aged ≥60 y.^11,12 In Finland, standard-dose (SD)-IIV4 vaccine (Vaxigrip Tetra®, Sanofi), which was first licensed in Europe in 2016, is recommended for those aged ≥65 y, children aged 6 months to 6 y, pregnant women, and people with comorbid conditions.^13,14 HD-IIV4 and SD-IIV4 are both quadrivalent, inactivated, split virion influenza vaccines. However, the HD vaccine contains 60 µg of hemagglutinin antigen (HA) per strain compared with 15 µg per strain for the SD vaccine.^12,13 Both vaccines have previously demonstrated acceptable safety profiles across age groups, with the majority of reactions, including headache, fever and injection site pain, being mild and occurring within the first three days following vaccination and resolving spontaneously shortly after onset (1 to 3 days).^12,13,15,16 Previously, the 2021/22 northern hemisphere (NH) EPSS for HD-IIV4 vaccine in Germany and SD-IIV4 vaccine in Finland used EDC with telephone reporting as back-up. The results did not suggest any clinically significant change in safety beyond that known or expected for these vaccines.⁷

Here, we report the EPSS during the NH 2022/23 influenza season for IIV4 vaccines in Germany and Finland with the overall aim of detecting any potential safety signals for these vaccines in the routine clinical care setting. The primary objective was to estimate for each vaccine the vaccinee reporting rate (RR) of suspected AEFI occurring ≤7 days post-vaccination in the overall population.

Methods

EPSS study design

This EPSS study assessed suspected AEFI reported by individuals receiving the HD-IIV4 vaccine in Germany and the SD-IIV4 vaccine in Finland during the NH 2022/23 influenza season. In each country, the EPSS included individuals who received one of the vaccines at the start of the 2022/23 influenza season. Vaccines were administered as per routine clinical practice in accordance with the product labeling. The healthcare professionals in Germany and Finland were selected based on their potential use of HD-IIV4 or SD-IIV4. Participants who attended the clinical practice sites for routine vaccination and who agreed to participate in the EPSS were included. In Germany, participants aged ≥60 years who received the HD-IIV4 vaccine were enrolled at ten sites between 6 October and 27 October 2022; safety data were collected until 10 November 2022. In Finland, participants aged ≥6 months received the SD-IIV4 vaccine at six sites between 12 October and 15 November 2022; safety data were collected until 29 November 2022. This study design was derived from a previous EPSS study carried out in Germany and Finland during the 2021/22 influenza season.⁷

The study was conducted in accordance with the Declaration of Helsinki, Good Epidemiological Practice, and the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance. No ethics committee submission was required in Finland for conducting EPSS. However, in Germany, independent ethics committee approval was obtained prior to the initiation of the EPSS program. Informed consent was not required because the EPSS relied on routine pharmacovigilance and voluntary spontaneous reporting.

Objectives

The primary objective was to estimate for each vaccine the vaccinee RR of suspected AEFI occurring ≤7 days post-vaccination. The secondary objectives were (1) to estimate the vaccinee RR occurring ≤7 days post-vaccination according to pre-defined age groups (≥6 months to <6 y, ≥6 to <13 y, ≥13 to <18 y, ≥18 to ≤65 y and >65 y) with the SD-IIV4 vaccine in Finland; (2) to estimate the vaccinee RR for serious suspected AEFI over the entire follow-up period in Finland and Germany; (3) to compare the vaccinee RR of suspected AEFI observed during the current EPSS with the rates reported during EPSS in the 2021/22 season in each country and with the rates reported in the Summary of Product Characteristics (SmPCs) for each vaccine.^12,13

Vaccines

In Germany, participants received HD-IIV4 vaccine (Efluelda®, Sanofi) containing 60 μg HA per influenza strain. In Finland, participants received SD-IIV4 vaccine (Vaxigrip Tetra®, Sanofi) containing 15 μg HA per strain. Influenza strains were those recommended for the NH 2022/23 influenza season: A/Victoria/2570/2019 (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.

Vaccination cards and AEFI reporting

Vaccination cards (VC) were distributed to the vaccinee and filled in by HCPs to document exposure to the vaccine (e.g., batch number, date of vaccination, age group. A copy of the VC was retained at the site so that the details could be transcribed into the EDC system. All participating HCPs were remotely trained on study procedures regarding vaccination cards and AEFI reporting.

AEFI were reported in the EDC (Viedoc 4.60), via the designated participant interface – the e-patient reported outcome (e-PRO) interface – into which the vaccinees or vaccinees’ parents/legal guardians logged in with their unique identification number and pin code (both provided in the VC). HCPs informed each vaccinee or vaccinee’s parents/legal guardians on the importance of reporting suspected AEFIs in the EDC system or via telephone, particularly those occurring within the first 7 days following vaccination, and instructed them on how to use the EDC system. The participants reported details for any AEFI they experienced in ‘real-time’ by selecting from a list of pre-specified adverse events or using open fields to report non-listed events, or no events (Supplementary methods). Alternatively, vaccinees or vaccinees’ parents/legal guardians could report AEFI by telephone to Sanofi Pharmacovigilance affiliates in Finland or Germany. All data were extracted from the pharmacovigilance database for statistical analyses.

Data collected

The medical dictionary for regulatory activities (MedDRA) was used to define AEFI by system organ class (SOC) and preferred term (PT). Vaccinees were asked to report the intensity of AEFI as mild, moderate, or severe. Serious AEFI were defined as those that resulted in death, were life threatening, required inpatient hospitalization or the prolongation of existing hospitalization, or resulted in the persistence of significant disability or incapacity.

Adverse Events of Interest (AEIs) as identified by the Pharmacovigilance Risk Assessment Committee (PRAC) were analyzed separately and classified as systemic reactions (fever [≥38°C], nausea, vomiting, malaise, headache, decreased appetite, myalgia and/or arthralgia, irritability/prolonged crying [aged <5 y]), injection-site reactions (i.e., pain, erythema, and swelling) and events indicative of allergic and hypersensitivity reactions, including rash and ocular symptoms.¹ The risk management plan (RMP) documents the risk management system necessary to identify, characterize and minimize the vaccine’s important risks, and was developed in accordance with Chapter ‘V.B.6.1. Risk Management Plan part III section Routine Pharmacovigilance activities’ in the Good Pharmacovigilance Practices Module V.^1,17 Sanofi as the Marketing Authorization Holder (MAH) for Efluelda® and Vaxigrip Tetra® vaccines holds the RMPs for these products in Europe. AEIs identified as potential risks as defined in the RMP were anaphylactic reaction, vasculitis, thrombocytopenia, and nervous system disorders such as convulsions (including febrile), Guillain-Barré syndrome, encephalitis/transverse myelitis, and neuritis. AEFI that did not qualify as AEIs or in the RMP were termed as ‘other AEFI.^1,17

Statistical analysis

The EPSS current interim guidance for seasonal influenza vaccines in the EU (EMA/PRAC/222346/2014) requires the system to be able to detect AEFI considered to be common (expected to occur with a reporting rate of ≥1%).¹ In each country, 1000 individuals vaccinated up to six weeks following the start of the EPSS were required to be included across the participating sites. This population size provides a >99% probability of collecting ≥1 report of a common AE. Descriptive statistics were used to summarize the data, including the vaccinee RR with associated two-sided 95% confidence intervals (CI). The vaccinee RR was calculated using the number of vaccinees who reported at least one suspected AEFI divided by the total number of vaccinees. The 95% CIs were calculated using the Clopper-Pearson exact CI. Data were summarized cumulatively by AEFI occurring ≤7 days and AEFI occurring during the entire reporting period (including those with missing time to onset). AEFI were also described by intensity, seriousness, and pre-defined age groups for the SD-IIV4 vaccine in Finland.

Results

Vaccinees

In Germany, 1041 VCs were distributed to adults aged ≥60 years who received HD-IIV4 vaccine. In Finland, 1001 VCs were distributed to children and adults who received SD-IIV4 vaccine. In Finland, most (971) vaccinees were aged ≥ 18 to <65 years; 28 were aged ≥65 years and two were aged ≥ 13 to <18 years. No vaccinees were aged <13 years.

In both countries, it was possible for vaccinees to receive COVID-19 vaccine at the EPSS site, or from elsewhere during 7 days after receiving IIV4 vaccine. In Germany 9.7% of vaccinees were co-administered a COVID-19 vaccine on the same day as the influenza vaccine and 0.1% of vaccinees in Finland received a COVID-19 vaccine on the same day.

HD-IIV4 in Germany

AEFI

During the follow-up period, 10 vaccinees reported 31 suspected AEFI, with a vaccinee RR of 0.96% (95% CI: 0.46, 1.76). The time to onset was known for 16 AEFI, of which 15 (93.8%) occurred ≤7 days post-vaccination, with a vaccinee RR of 0.58% (95% CI: 0.21, 1.25) (Table 1). Of the 31 AEFI, three were of mild intensity (reported by three vaccinees; RR 0.29%, 95% CI: 0.06, 0.84), 12 were of moderate intensity (reported by four vaccinees; RR 0.38%, 95% CI: 0.10, 0.98) and the remaining AEFI were of unknown intensity. There were no AEFI reported with severe intensity. There was one serious AEFI (angina pectoris), and all other AEFI were non-serious (RR 0.10%, 95% CI: 0.00, 0.53) (Table 1).

Table 1. Overview of AEFI reporting in Germany (HD-IIV4) and Finland (SD-IIV4) in 2022/23 influenza season.

	Vaccinees reporting ≥ 1 suspected AEFI, n	Number of AEFI	Vaccinee RR
HD-IIV4 in Germany, VCs distributed, n = 1041
AEFI ≤7 d of vaccination	6	15^a	0.58 (0.21, 1.25)
AEFI during the entire follow-up period^b	10	31	0.96 (0.46, 1.76)
By intensity^c
Mild	3	3	0.29 (0.06, 0.84)
Moderate	4	12	0.38 (0.10, 0.98)
Severe	0	0	0.00 (0.00, 0.35)
Serious AEFI	1	1	0.10 (0.00, 0.53)
SD-IIV4 in Finland, VCs distributed, n = 1001
AEFI ≤7 d of vaccination	48	133^d	4.80 (3.56, 6.31)
AEFI during the entire follow-up period^e	51	142	5.09 (3.82, 6.64)
By intensity^f
Mild	39	80	3.90 (2.78, 5.29)
Moderate	25	49	2.50 (1.62, 3.66)
Severe	2	5	0.20 (0.02, 0.72)
Serious AEFI	0	0	0.00 (0.00, 0.37)

AEFI, adverse event following immunization; AEI, adverse events of interest; HD, high-dose; IIV4, quadrivalent inactivated split-virion influenza vaccine; SD, standard dose; RR, reporting rate, VC, vaccination card.

^aA total of seven AEFI occurred on the same day or the following day after vaccination; four AEFI occurred 2 d post-vaccination, and four AEFI occurred within 3–4 d post-vaccination.

^bThe time to onset was known for 16/31 AEFI.

^cFour vaccinees reported 16 AEFI of unknown intensity (RR 0.38 [0.10, 0.98]).

^dA total of 117 AEFI occurred on the same day or the following day after vaccination, nine AEFI occurred 2 d post-vaccination and seven AEFI occurred within 4 d post-vaccination.

^eEight vaccinees reported eight AEFI of unknown intensity (RR0.80 [0.35, 1.57]).

^fThe time to onset was known for 133/142 AEFI.

AEIs

Among AEFI, 71.0% (22/31) were AEIs. All 10 vaccinees reporting an AEFI reported at least one AEI, with a vaccinee RR of 0.96% (95% CI: 0.46, 1.76). The time to onset was known for 13 AEIs, of which 12 were reported by six vaccinees ≤7 days post-vaccination (RR 0.58%, 95% CI: 0.21, 1.25). The most frequently reported AEIs overall were injection site reactions, myalgia, and malaise (Table 2).

Table 2. Reporting of AEIs by SOC in Germany (HD-IIV4) in 2022/23 influenza season.

	VCs distributed, n = 1041
	≤7 d post-vaccination^a			During entire follow-up period^a
	n	nAEI	Vaccinee RR (95% CI)	n	nAEI	Vaccinee RR (95% CI)
Any AEI	6	12^b	0.58 (0.21, 1.25)	10	22	0.96 (0.46, 1.76)
Injection site reaction	5	7	0.48 (0.16, 1.12)	8	10	0.77 (0.33, 1.51)
Headache	1	1	0.10 (0.00, 0.53)	1	1	0.10 (0.00, 0.53)
Myalgia	1	1	0.10 (0.00, 0.53)	3	4	0.29 (0.06, 0.84)
Fever	0	0	0.00 (0.00, 0.35)	2	2	0.19 (0.02, 0.69)
Malaise	1	1	0.10 (0.00, 0.53)	2	3	0.19 (0.02, 0.69)
Arthralgia	0	0	0.00 (0.00, 0.35)	0	0	0.00 (0.00, 0.35)
Nausea	1	1	0.10 (0.00, 0.53)	1	1	0.10 (0.00, 0.53)
Decreased appetite	0	0	0.00 (0.00, 0.35)	0	0	0.00 (0.00, 0.35)
Events indicative of allergic and hypersensitivity reactions^c	1	1	0.10 (0.00, 0.53)	1	1	0.10 (0.00, 0.53)

AEI, adverse events of interest; CI, confidence interval; HD, high-dose; IIV4, quadrivalent inactivated split-virion influenza vaccine; SD, standard dose; n, number of vaccinees; nAEI, number of AEIs; RR, reporting rate; SOC, system organ class; VC, vaccination card.

^aThe time to onset was known for 13/22 AEIs; 1 AEI of injection site reaction was reported >7 d after vaccination.

^bA total of seven AEIs occurred on the same day or the following day after vaccination; four AEIs occurred within 2 d post-vaccination and one AEI occurred 4 d post-vaccination.

^cIncluding rash and ocular symptoms.

‘Other AEFI

There were nine ‘other’ AEFI reported by five vaccinees during the follow-up period (RR 0.48%, 95% CI: 0.16, 1.12). Time to onset was known for three AEFI reported by two vaccinees, all of which occurred ≤7 days post-vaccination (RR 0.19%, 95% CI: 0.02, 0.69) (Table 3).

Table 3. Reporting of ‘other’ AEFI by PT in Germany (HD-IIV4) in 2022/23 influenza season.

	VC distributed n = 1041
	≤7 d post-vaccination^a			During entire follow-up period^a
	n	nAEFI	Vaccinee RR (95% CI)	n	nAEFI	Vaccinee RR (95% CI)
‘Other’ AEFI	2	3^b	0.19 (0.02, 0.69)	5	9	0.48 (0.16, 1.12)
Nasopharyngitis	2	2	0.19 (0.02, 0.69)	2	2	0.19 (0.02, 0.69)
Cough	1	1	0.10 (0.00, 0.53)	1	1	0.10 (0.00, 0.53)
Chills	0	0	0.00 (0.00, 0.35)	3	3	0.29 (0.06, 0.84)
Dyspnoea	0	0	0.00 (0.00, 0.35)	1	1	0.10 (0.00, 0.53)
Angina pectoris	0	0	0.00 (0.00, 0.35)	1	1	0.10 (0.00, 0.53)
Listless	0	0	0.00 (0.00, 0.35)	1	1	0.10 (0.00, 0.53)

AEFI, adverse event following immunization; CI, confidence interval; HD, high-dose; IIV4, quadrivalent inactivated split-virion influenza vaccine; n, number of vaccinees; nAEFI, number of AEFI; PT, preferred Term; RR, reporting rate; VC, vaccination card.

^aThe time to onset was known for 3/9 ‘other’ AEFI.

^bAll three AEFI occurred within 3–4 d post-vaccination.

As per protocol, the calculation of time to onset relies on the vaccination date recorded in the VC. However, a subject reporting an AEFI of angina pectoris by telephone did not provide the VC number, hindering the link to VC data and resulting in the event being classified as “unknown time to onset.” Nevertheless, based on details in the case narrative, the event occurred 6 hours post-vaccination with HD-IIV4.

SD-IIV4 in Finland

AEFI

Of the 1001 vaccinees, 51 vaccinees reported a total of 142 AEFI (RR 5.09%, 95% CI: 3.82, 6.64). The time to AEFI onset was known for 133 (93.7%) of the 142 AEFI, all of which occurred ≤7 days of vaccination (RR 4.80%, 95% CI: 3.56, 6.31) (Table 1). Among the AEFI that occurred ≤7 days post-vaccination, 88.0% (117/133) occurred on the same day or the day after vaccination. No AEFI were reported by the two vaccinees aged ≥ 13 to <18 y. Among 971 vaccinees aged ≥ 18 to <65 y, 48 reported 137 AEFI (RR 4.94%, 95% CI: 3.67, 6.50). Among the 28 vaccinees aged ≥65 y, three reported five AEFI (RR 10.71%, 95% CI: 2.27, 28.23) (Supplementary Table S1). A total of 80/142 AEFI (56.3%) were mild intensity (RR 3.90%, 95% CI 2.78, 5.29), 49/142 (34.5%) were moderate intensity (RR 2.50%, 95% CI: 1.62, 3.66), and 5 (3.5%) were severe intensity (RR 0.20%, 95% CI: 0.02, 0.72). Four severe events were AEIs and one was an ‘other’ AEFI. No serious AEFI were reported (Table 1).

AEIs

Among AEFI, 86.6% (123/142) were AEIs, which were reported by 50 vaccinees (RR 5.00%, 95% CI: 3.73, 6.53). The time to AEFI onset was known for 114 AEIs and all of them occurred within 7 days post-vaccination (RR 4.70%, 95% CI: 3.47, 6.20) (Table 4). Of the 114 AEIs, 102 AEFI (89.5%) occurred on the same day or the day after vaccination. Among 971 vaccinees aged ≥ 18 to <65 y, 47 reported 118 AEIs (RR 4.84%, 95% CI: 3.58, 6.38) (Supplementary Table S1). Injection site reaction was most the most frequently reported AEI (62/123; RR 3.90%, 95% CI: 2.78, 5.29) (Table 4). Intensity was reported for 116 of 123 AEIs (94.3%), of which 58.5% (72/123) were mild (RR 3.70%, 95% CI 2.62, 5.06), 32.5% (40/123) were moderate (RR 2.40%, 95% CI: 1.54, 3.55), and 3.3% (4/123) were severe (RR 0.20%, 95% CI: 0.02, 0.72). Severe AEIs were myalgia, headache, and arthralgia.

Table 4. Reporting of AEIs by SOC in Finland (SD-IIV4) in 2022/23 influenza season.

	VCs distributed, n = 1001
	≤7 d post-vaccination^a			During entire follow-up period^a
	n	nAEI	Vaccinee RR (95% CI)	n	nAEI	Vaccinee RR (95% CI)
Any AEI	47	114^b	4.70 (3.47, 6.20)	50	123	5.00 (3.73, 6.53)
Injection site reaction	36	56	3.60 (2.53, 4.94)	39	62	3.90 (2.78, 5.29)
Headache	13	13	1.30 (0.69, 2.21)	13	13	1.30 (0.69, 2.21)
Myalgia	15	15	1.50 (0.84, 2.46)	16	16	1.60 (0.92, 2.58)
Fever	8	8	0.80 (0.35, 1.57)	8	8	0.80 (0.35, 1.57)
Malaise	6	6	0.60 (0.22, 1.30)	6	6	0.60 (0.22, 1.30)
Arthralgia	5	5	0.50 (0.16, 1.16)	5	5	0.50 (0.16, 1.16)
Nausea	4	4	0.40 (0.11, 1.02)	5	5	0.50 (0.16, 1.16)
Decreased appetite	2	2	0.20 (0.02, 0.72)	2	2	0.20 (0.02, 0.72)
Events indicative of allergic and hypersensitivity reactions^c	3	5	0.30 (0.06, 0.87)	4	6	0.40 (0.11, 1.02)

AEI, adverse events of interest; CI, confidence interval; HD, high-dose; IIV4, quadrivalent inactivated split-virion influenza vaccine; SD, standard dose; n, number of vaccinees; nAEI, number of AEIs; RR, reporting rate; SOC, system organ class; VC, vaccination card.

^aThe time to onset was known for 114/123 AEIs.

^bA total of 102 AEIs occurred on the same day or the following day after vaccination and 12 AEIs occurred within 4 d of vaccination.

^cIncluding rash and ocular symptoms.

‘Other AEFI’

A total of 13 vaccinees reported 19 ‘other’ AEFI (RR 1.30%, 95% CI: 0.69, 2.21) (Table 5). All 19 AEFI occurred ≤7 days post-vaccination, of which 15/19 (78.9%) occurred on the same day or the day after vaccination. All ‘other’ AEFI were reported in vaccinees aged ≥ 18 to <65 y (Supplementary Table S1).

Table 5. Reporting of ‘other’ AEFI by PT in Finland (SD-IIV4) in 2022/23 influenza season.

	VCs distributed, n = 1001 ≤7 d of vaccination^a
	n	nAEFI^a	Vaccinee RR (95% CI)
‘Other’ AEFI	13	19^b	1.30 (0.69, 2.21)
Nasopharyngitis	4	4	0.40 (0.11, 1.02)
Influenza	2	2	0.20 (0.02, 0.72)
Feeling cold	4	4	0.40 (0.11, 1.02)
Lymph node pain	1	1	0.10 (0.00, 0.56)
Lymphadenopathy	1	1	0.10 (0.00, 0.56)
Diarrhoea	1	1	0.10 (0.00, 0.56)
Toothache	1	1	0.10 (0.00, 0.56)
Oropharyngeal pain	1	1	0.10 (0.00, 0.56)
Sneezing	1	1	0.10 (0.00, 0.56)
Blood urine present	1	1	0.10 (0.00, 0.56)
Body temperature decreased	1	1	0.10 (0.00, 0.56)
Back pain	1	1	0.10 (0.00, 0.56)
Insomnia	1	1	0.10 (0.00, 0.56)

AEFI, adverse event following immunization; CI, confidence interval; IIV4, quadrivalent inactivated split-virion influenza vaccine; n, number of vaccinees; nAEFI, number of AEFI; PT, preferred Term; RR, reporting rate; SD, standard dose; VC, vaccination card.

^aThe time to onset was known for all ‘other’ AEFI and all occurred ≤7 d after vaccination.

^bA total of 15 AEFI occurred on the same day or the following day after vaccination and 4 AEFI occurred within 4 d post-vaccination.

Comparison of 2022/23 and 2021/22 seasons

HD-IIV4 in Germany

There were 903 vaccinees in the 2021/22 EPSS in Germany and 1041 vaccinees in the current season. For the AEFI that occurred ≤7 days after vaccination, the vaccinee RR was 0.58% (95% CI: 0.21, 1.25) in 2022/23 (Table 1) and 1.88% (95% CI: 1.10, 3.00) in 2021/22.⁷ There were no severe AEFI in 2022/23 compared with 16 severe AEFI in 2021/22. Among the AEFI that were common in both seasons, all presented with either similar or lower RRs than the previous season.⁷ AEFI reported in the current season but not in the previous season presented with RRs below or within the expected frequencies listed in the SmPC (vaccination site swelling, neck pain, asthenia, rash, cough, listless) or were listed in SmPC with unknown frequency (dyspnea and angina pectoris). Nasopharyngitis was newly reported in the current season but not listed in the SmPC.

SD-IIV4 in Finland

There were 1001 vaccinees in the current season and 1000 in the 2021/22 EPSS. For AEFI occurring ≤7 days, the vaccinee RR was 4.80% (95% CI: 3.56, 6.31) in 2022/23 (Table 1), compared with 4.90% (95% CI: 3.65, 6.43) in 2021/22.⁷ Among the AEFI that were common in both seasons, RRs were numerically higher for the current season than in the previous season for only vaccination site erythema (1.80% [95% CI: 1.07, 2.83] vs. 0.50% [95% CI: 0.16, 1.16], respectively) and vaccination site swelling (1.10% [95% CI: 0.55, 1.96] vs. 0.40% [95% CI: 0.11, 1.02], respectively).⁷ AEFI reported in the current season but not in the previous season presented with RR below or within the expected frequencies listed in the SmPC (hypersensitivity, feeling cold and diarrhea). There were 10 AEFI newly reported in the current season that were not listed in the SmPC, which were single events of dry eye, eye irritation, periorbital swelling, and swelling of eyelid, lymph node pain, toothache, sneezing, body temperature decreased, and insomnia, as well as four events of nasopharyngitis.

Discussion

In Germany and Finland during the NH 2022/23 influenza season, the results of the EPSS were consistent with the established safety profiles of seasonal influenza vaccines (IIV3 and IIV4). In Germany, ten vaccinees reported 31 AEFI during the follow-up period, and among 16 AEFI with known time to onset (six vaccinees), 15 AEFI occurred within ≤7 days post-vaccination, at a vaccinee RR of 0.58% (95% CI: 0.21, 1.25). In Finland, 51 vaccinees reported a total of 142 AEFI, and among 133 AEFI with known time to onset (48 vaccinees) all occurred ≤7 days post-vaccination, at a vaccinee RR of 4.80% (95% CI: 3.56, 6.31). However, it should be noted that there were no vaccinees aged <6 y, and only two were aged ≥ 13–<18 y. In general, published rates of spontaneous AEFI reports with other seasonal influenza vaccines range from 20 to 90 reports per 1,000,000 people vaccinated.^18–21

The reporting rates were lower in Germany compared with Finland. This may be explained by the demographic differences between the study populations. For example, vaccinees in Germany were older and therefore displayed different physiological characteristics to patients aged 6 months to 18 years. Additionally, older adults have been identified at high risk of digital exclusion,²² and, in this EPSS, might be less prone to report an AEFI via the EDC system. In Germany, AEFI were mild or moderate in intensity. There was one report of angina pectoris in a 76-year-old vaccinee occurring 6 hours after administration of the HD-IIV4 vaccine that was considered serious; however, as medical history, concomitant medication, and alternative etiologies were not reported, the event cannot be attributed solely to the influenza vaccine. In Finland, most AEFI were mild or moderate in intensity, and two vaccinees reported five severe AEFI, which were myalgia, headache, fatigue, arthralgia, and feeling cold. In Germany 71.0% of reports were AEIs, and 86.6% in Finland; in both countries, most were injection site reactions. In Finland, vaccination site erythema and vaccination site swelling were more common the season assessed than during the previous season. There was no particular reporting pattern in terms of intensity grades observed for any of the AEIs.

The HD-IIV4 vaccine has been used in Germany since the 2021/22 season, and the SD-IIV4 vaccine has been used in Finland for several seasons. In the current season in Germany, the overall vaccinee RR was lower than the 2021–2022 influenza season, although the CIs do overlap. However, across both seasons, a similar trend was observed for vaccinee RR within seven days post-vaccination.⁷ There were 10 AEFI that were not reported in the 2021/22 season, although all but nasopharyngitis were listed in the SmPC. Among the AEFI that were common in both seasons, all presented with either similar or lower RRs than the 2021–2022 influenza seasons. In Finland, while there was similarity between seasons in vaccinee RRs for aggregate AEFI, the vaccinee RRs for vaccination site erythema and vaccination site swelling were higher during the 2022/23 season than in previous seasons.⁷ There were 10 AEFI reported in the current season that were not listed in the SmPC, although these did not raise any additional safety issues or concerns.⁷

In Finland, EPSS of the SD-IIV4 vaccine has been conducted since the 2018/19 season, using various data collection methods.^7,23 For example, when e-mail reporting was used during the 2018/19 season, the 7-day AEFI rate was only 5.3% (95% CI: 3.9, 6.7); and in the 2019/20 season, when pre-paid envelopes and telephone reporting was used but not e-mail, the 7-day AEFI rate was 12.5% (95% CI: 10.4, 14.7).^12,24 Although reporting rates between seasons are not directly comparable, experience with different methods has enabled the advancement of EDC systems that are easily accessible to vacinees, local sites, and pharmacovigilance professionals. Indeed, postal reporting in Finland during 2019/20 represented additional work for vaccinees, particularly in cases of multiple events at different time points, so in subsequent seasons in Finland, EPSS studies used EDC reporting with telephone back-up.

A limitation of the study was that in Germany the time to onset was known for only half of the reported AEFI. However, for AEFI overall, including those with a missing time of onset, the vaccinee RR was 0.96% (95% CI: 0.46, 1.76), which is lower than the overall rate reported in the 2021/22 EPSS in Germany (RR 2.10%, 95% CI: 1.27, 3.27).⁷ A further limitation was the lack of representation of vacinees aged <18 years in Finland. The main limitation of the study was that all AEFI were self-reported by vaccinees or their legal guardians and were not medically confirmed. This limitation was also noted in the previously published EPSS study conducted in Germany and Finland during the 2021/22 influenza season.⁷ To avoid bias in the collection of safety data, there was no possibility to follow-up with individuals at the site level. Lastly, 9.7% of participants in Germany and 0.1% of participants in Finland received a COVID-19 vaccine on the same day as the influenza vaccine, while others may have received COVID-19 vaccine either prior or post-influenza vaccination. Consequently, determining the vaccine responsible for the symptoms could be confounded among these vaccinees.

Conclusions

Building on experience over influenza seasons, the NH 2022/23 EPSS for HD-IIV4 was conducted in Germany and for SD-IIV4 vaccine was conducted in Finland. The results for both vaccines were consistent with previous seasons and with the established safety profile of IIV4 vaccines.

Author contributions

MAAM, SG-B, SG, TGC, RMB and CM contributed to the concept or design of the study. CM contributed to the data acquisition. MAAM, SG-B, TGC, RMB, MN, JS and CM contributed to the data analysis or interpretation. All authors contributed to 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.

Acknowledgments

The authors would like to thank all participants who took part in the FLU00171 study, and the Sanofi and Zifo EPSS study team members. The authors also thank Isabel Grégoire, PhD (Sanofi) for editorial assistance and manuscript coordination. Medical writing and editorial assistance were provided by Annick Moon PhD, on behalf of inScience Communications, Springer Healthcare Ltd, UK. Funding for this assistance was provided by Sanofi.

Disclosure statement

MAAM, SG-BG, SG, TGC, RMB and CM are employees of Sanofi and may hold shares and/or stock options in the company. MN has received honoraria from advisory boards of Eli Lilly, Pfizer and Novartis. JS received fees for conferences and scientific advice from Merck/MSD, Sanofi, Seqirus, Pfizer, MSD, AstraZeneca, GSK, Janssen, Novavax and Bavarian Nordic.

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 patient 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. Patient level data will be anonymized and study documents will be redacted to protect the privacy of our trial participants. Further details on Sanofi’s data sharing criteria, including required permissions to access the data, eligible studies, and process for requesting access can be found at: https://www.vivli.org/.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2024.2322196.

Additional information

Funding

This study was funded by Sanofi.