Challenges and future perspectives of enhanced passive safety surveillance of influenza vaccines in Europe

Abstract

Postmarketing surveillance is critical for confirming the safety profile of vaccines following regulatory approval. This article contributes to the ongoing discussion on safety surveillance strategies for seasonal influenza vaccines in Europe. We examine the implementation of enhanced passive safety surveillance (EPSS) for seasonal influenza vaccines from season 2015/16 through season 2023/24, as conducted by a Marketing Authorization Holder in accordance with European Medicines Agency guidelines. We describe the evolution of data collection methods of EPSS studies conducted across nine seasons in Finland, United Kingdom, Republic of Ireland, Denmark, and Germany with different influenza vaccine formulations. Exposure data were prospectively collected in vaccination cards at the time of vaccination, while safety data collection evolved from telephone calls to electronic reporting systems. The use of an electronic system in recent seasons facilitated adverse drug reaction reporting by the vaccinees and improved real-time monitoring and accurate data collection. Operational challenges included country and site selection constraints and difficulty achieving target sample sizes and age group representation within short recruitment windows. Reporting rates varied across seasons, countries, and vaccine formulations, potentially influenced by factors such as vaccine reactogenicity, population demographics, and reporting behaviors. Future perspectives suggest the need for a unified Europe-wide safety surveillance system to enhance collaboration among regulatory bodies, public health agencies, and vaccine manufacturers, ultimately contributing to a more robust and reliable safety framework for influenza vaccines.

Plain language summary

Safety monitoring of seasonal influenza vaccines in Europe

Ensuring the safety of influenza vaccines after they are approved for use is crucial for public health. Our article examines safety monitoring strategies for seasonal influenza vaccines in Europe from the perspective of an influenza vaccine manufacturer. We describe the implementation of a safety monitoring program for seasonal influenza vaccines in five European countries (Finland, United Kingdom, Ireland, Denmark, and Germany) from season 2015/16 through season 2023/24. This program, called “enhanced passive safety surveillance,” evolved over time to better monitor vaccine safety. When people got their flu shots, they received a card with information about reporting adverse events they may experience after vaccination. In recent years, people could report adverse events online, which made reporting faster and more reliable while helping the manufacturer to process the data more efficiently. However, the program faced several challenges. Sometimes it was difficult to find clinics that wanted to collaborate and to get enough people at different ages to participate in the studies. The number of reported adverse events varied depending on the country, the vaccine type, and the year. We believe that a unified safety surveillance system in Europe could offer various advantages by helping health agencies and vaccine companies working better together. By improving how we monitor vaccine adverse events, we can identify potential safety issues more quickly and take steps to prevent them. It could also make people feel more confident about getting flu vaccines. An efficient monitoring system helps keep vaccines safe for everyone.

Keywords

enhanced safety surveillance pharmacovigilance seasonal influenza vaccine

Introduction

Seasonal influenza affects approximately 1 billion individuals worldwide each year, with 3 to 5 million cases progressing to severe illness and resulting in 290,000 to 650,000 deaths attributed to influenza-related respiratory complications.¹ Influenza vaccination is crucial for reducing both mortality and morbidity associated with influenza disease in communities worldwide, especially among vulnerable populations such as the young children, elderly, and individuals with compromised immune systems.^2,3 While clinical trials establish the safety of vaccines before market approval, postmarketing evidence plays an important role in identifying rare adverse events that might not surface during initial trials as well as obtaining long-term safety evidence.⁴ Regulatory agencies mandate postmarketing surveillance to continually evaluate the benefit–risk profile of vaccines, influencing decisions on product labeling, product safety warnings, and potential marketing authorization withdrawals.⁵

The purpose of this article is to contribute to the discussion on the safety surveillance of seasonal influenza vaccines. This article presents the experience of Sanofi, a marketing authorization holder (MAH), in conducting safety surveillance of seasonal influenza vaccines across the European continent (including the United Kingdom (UK)) since 2015, detailing methodologies, challenges, and lessons learned. The article explores safety surveillance systems utilized both within and outside Europe and proposes considerations for future safety surveillance strategies for influenza vaccines.

Safety surveillance of seasonal influenza vaccines in Europe

Pharmacovigilance systems are essential for monitoring the safety of medicinal products, including vaccines, throughout their lifecycle. These systems involve coordinated efforts between regulatory authorities and MAHs to ensure comprehensive safety monitoring and protection of public health. In Europe, the European Medicines Agency (EMA) coordinates the pharmacovigilance system. EMA is responsible for operating and maintaining the EudraVigilance database used for collecting and analyzing reports of suspected adverse drug reactions (ADR); evaluating safety signals through the Pharmacovigilance Risk Assessment Committee (PRAC); and ensuring that MAHs comply with pharmacovigilance obligations. EMA also develops and enforces Good Pharmacovigilance Practices, which provide a harmonized framework for all stakeholders, ensuring consistent monitoring, risk assessment, and communication of safety concerns across the European Union (EU).^5,6 Of note, since Brexit and effectively after January 2021, the Medicines and Healthcare products Regulatory Agency (MHRA) has been solely responsible for medicines regulation in the UK, operating independently from the EMA. EU countries and the UK have also established robust national pharmacovigilance systems that contribute to the broader safety-monitoring framework. For example, the Denmark’s ADR Reporting System, Finland’s National Adverse Drug Reaction Register, Germany’s ADR Reporting System managed by PEI and BfArM, Ireland’s HPRA Adverse Reaction Reporting System, and UK’s Yellow Card Scheme all provide mechanisms for safety monitoring of medicines and vaccines (Supplemental Table 1). These national systems, typically offering online and other reporting methods, collect and analyze data on suspected adverse reactions to identify potential safety concerns and inform necessary actions, with most feeding into the broader EudraVigilance database maintained by EMA. As a MAH, Sanofi maintains a comprehensive pharmacovigilance system and collaborates with health authorities and stakeholders to ensure safety of all products. This system encompasses continuous safety monitoring through receipt of spontaneous reports, literature reviews, and postauthorization safety studies (PASS) to further evaluate the safety profile in real-world settings. The company continuously collects and analyzes data on adverse events, conducts signal detection using advanced statistical methods to identify potential safety concerns, and regularly evaluates the benefit–risk profile of medicinal products. Sanofi fulfills regulatory obligations by submitting periodic safety update reports to authorities and conducting postmarketing studies, including enhanced passive safety surveillance (EPSS) for seasonal influenza vaccines described in more details in this article.

Seasonal influenza vaccines require additional safety surveillance practices, due to their annual strain updates, complementing the standard pharmacovigilance processes described above. Influenza viruses constantly undergo antigenic evolution through antigenic drift in their surface proteins, prompting the World Health Organization (WHO) to monitor the evolution of influenza viruses and recommend vaccine reformulations for each northern and southern hemisphere influenza season.^7,8 Consequently, every year, vaccine manufacturers produce influenza vaccines with minor modifications based on those recommendations. This annual reformulation creates challenges for safety monitoring because the pharmacovigilance systems must be capable of detecting potential changes in the reactogenicity profile of each season’s new vaccine formulation before the peak influenza immunization period.

Regulatory requirements for seasonal influenza vaccines from EMA have changed over time. Historically, MAHs were required to conduct small-scale clinical trials before each season, but these were deemed insufficiently informative due to their limited sample size and, since 2015, were no longer required in the EU.⁹ Starting in the influenza season 2015/16, EMA introduced a requirement of enhanced safety surveillance for seasonal influenza vaccines. This new approach aimed to rapidly detect clinically significant changes in the frequency and/or severity of expected reactogenicity in different age groups compared to what was known or expected with the previous vaccine composition. Reactogenicity represents the immediate physical symptoms that develop after vaccination as a result of the inflammatory immune response.¹⁰ Monitoring these events is important because a change in the reactogenicity profile may indicate a potential for more serious risks as exposure to the vaccine increases over the season.

The enhanced safety surveillance focuses on reactogenicity events expected to be common and is not designed to identify and quantify rare adverse events, as this would require large sample sizes that would make near real-time data collection prohibitive. Rare adverse events should be monitored via routine pharmacovigilance activities (e.g., signal detection) and, if necessary, evaluated by target PASS studies.¹¹

Based on the EMA’s 2014 “Interim guidance on enhanced safety surveillance for seasonal influenza vaccines in the EU,” MAHs with an authorized influenza vaccine in the EU are required to implement one out of three methods of enhanced safety surveillance: active, passive, or data mining. Active surveillance consists of a PASS with defined cohorts actively monitored at 7 days postimmunization (or up to 14 days for a live attenuated vaccine).¹¹ Active surveillance can be resource intensive and operationally challenging. The enhanced passive surveillance aims to rapidly estimate vaccine usage and facilitate passive ADR reporting and is considered part of routine pharmacovigilance activities (as per Risk Management Plan (RMP)).¹¹ Passive surveillance typically experiences underreporting and variable data quality, due to the voluntary nature of ADR reporting. It also lacks accurate estimation of the total number of vaccinees, which are crucial for calculating reporting rate. However, enhanced surveillance features are designed to mitigate these limitations. Additionally, data mining or other use of electronic health record data leverage large datasets to identify patterns, trends, and potential safety signals, enabling their utilization for safety surveillance.¹¹ However, many of the events of interest may not require medical visits and, hence, would not be available in electronic health care records. Moreover, real-time or near-real-time monitoring is impeded by delays in data availability. Looking ahead, EMA plans to further refine these recommendations with a concept paper and an update on the guidance in 2025, involving a public consultation phase.^12,13 Consequently, in March 2024, EMA/PRAC announced a waiver on the requirement to submit enhanced safety surveillance data for all seasonal influenza vaccines for the season 2024/25, while the guidance undergoes review.¹³

MAH’s experience with passive safety surveillance of seasonal influenza vaccines in Europe

Sanofi has conducted nine EPSS studies, according to EMA’s 2014 guidance, in Finland, the UK, Republic of Ireland, Denmark, and Germany, with different influenza vaccines formulations (trivalent/quadrivalent and standard dose/high dose) from season 2015/16 through season 2023/24. Following Brexit, enhanced safety surveillance remained a requirement in the UK under MHRA regulations. We continued to use the principles outlined in EMA’s 2014 guidance as a reference for conducting EPSS in the UK. The results of the EPSS were systematically communicated to regulatory authorities through established pharmacovigilance reporting channels and, as part of the company’s transparency policy, Sanofi published EPSS findings in peer-reviewed scientific journals, making the safety data available to the broader scientific community and healthcare professionals.^14–22

Setting and population

In each season, the EPSS was carried out in routine clinical care settings (ambulatory and non-ambulatory); therefore, the decision to vaccinate remained entirely at the discretion of the healthcare professional (HCP) and was not influenced by the surveillance implementation. Vaccination sites were selected from each country prior to the influenza season, based on the potential use of the respective vaccine brand and the HCPs’ willingness to participate in the EPSS. Remote training sessions were conducted for HCPs, acquainting them with study procedures. Individuals seeking vaccination at the selected sites and agreeing to participate in the EPSS were included and composed the exposed population (the requirement for vaccinees or their legally accepted representative to sign informed consent varied among countries, in accordance with local regulations and ethical guidelines).

Safety data collection

The “passive” nature of the surveillance relied on spontaneous (or unsolicited) reporting of ADRs submitted by HCPs, participants (vaccinees), or caregivers, in accordance with pharmacovigilance (PV) practices, as opposed to solicited ADRs. The safety collection focused on adverse events of interest (AEI) as defined by PRAC (fever (⩾38°C), nausea, vomiting, malaise, headache, decreased appetite, myalgia and/or arthralgia, irritability (for children under 5 years of age), prolonged crying (for children under 5 years of age), injection-site reactions (e.g., pain, erythema, swelling), rash, events indicative of allergic and hypersensitivity reactions, including ocular symptoms), with dedicated fields for these events in the ADR reporting forms (Supplemental Material presents an example of ADR form in English that was translated into each country’s official language). However, all reported ADRs, not just AEIs, were collected and processed by PV staff. To ensure timely detection of potential safety concerns, the surveillance strategy also included weekly reviews of both vaccine coverage and accumulated ADR data.

Enhanced safety surveillance features

The safety surveillance was enhanced by distinct features. First, at the time of vaccination, HCPs explained the importance of reporting ADRs, particularly those occurring within 7 days postvaccination. Second, the vaccinee received a Vaccination Card (VC) containing instructions on reporting an ADR and exposure data including vaccination date, age group, vaccine batch, co-administration of COVID-19 vaccine, when applicable. In addition, the VC included a unique vaccinee identifier, enabling the link of a vaccine administration to a potential ADR report (Supplemental Material presents an example of VC in English that was translated into each country’s official language). Finally, the ADR reporting was facilitated, particularly in recent seasons with the implementation of an electronic system for safety data collection (Figure 1).

Figure 1.

Data collection in the enhanced passive safety surveillance conducted by Sanofi in Europe.

Strengths and challenges of data collection

Table 1 presents the characteristics of data collection in each EPSS implemented by Sanofi and highlights the strengths and challenges. In all seasons, the exposure data (i.e., vaccine administered to individuals) was recorded in a VC, with the same data promptly entered into an electronic data capture (EDC) system by the HCPs. This approach offered real-time monitoring of enrolled vaccinees and well-documented exposure data.

Table 1.

Exposure and safety data collection from season 2015/16 through season 2023/24 for enhanced passive safety surveillance.

Season	Vaccine and country	Exposure data collection	Safety data collection	Strengths (+) and challenges (−)
2015/16¹³	TIV/Vaxigrip Finland and UK TIV/Intanza UK	Data collected on vaccination cards and entered into an EDC system	Telephone	(+) Exposure data well documented and monitored on a real-time basis. (−) ADR reporting via telephone likely led to underreporting.
2016/17¹⁴	TIV/Vaxigrip Ireland and UK TIV/Intanza UK	Data collected on vaccination cards and entered into an EDC system	Telephone	(+) Exposure data well documented and monitored on a real-time basis. (−) ADR reporting via telephone likely led to underreporting.
2017/18¹⁵	TIV/Vaxigrip Ireland QIV/VaxigripTetra Ireland TIV/Intanza UK	Data collected on vaccination cards and entered into an EDC system	Telephone	(+) Exposure data well documented and monitored on a real-time basis. (−) ADR reporting via telephone likely led to underreporting.
2018/19¹⁶	TIV/Vaxigrip Denmark QIV/VaxigripTetra Finland	Data collected on vaccination cards and entered into an EDC system	Telephone and email	(+) Exposure data well documented and monitored on a real-time basis. (−) Email ADR reports resulted in poor data quality, with participants often not responding to follow-up emails.
2019/20¹⁷	QIV/VaxigripTetra Finland	Data collected on vaccination cards and entered into an EDC system	Telephone and ADR form by mail (prepaid envelope)	(+) Exposure data well documented and monitored on a real-time basis. (−) Poor quality data of reports via mail (−) ADR forms via mail required additional work for the vaccinees, especially in the case of multiple events at different time points
	TIV-HD/Fluzone HDUK	Number of doses administered was provided to MAH by participating hospitals	UK Yellow Card Scheme	(−) Poor documentation of exposure data by the hospital staff(−) Inadequate management of EPSS by each hospital contributed to ADR underreporting
2020/21¹⁸	QIV/VaxigripTetraFinland	Data collected on vaccination cards and entered into an EDC system	ADR form via an electronic system	(+) Exposure data well documented and monitored on a real-time basis.(+) Use of an electronic ADR form simplified data collection and management.(+) The electronic system enabled safety concerns to be rapidly processed by local pharmacovigilance staff through automatic notifications once a new ADR was reported.(−) Disruption to health-seeking behaviour and staffing/routines in clinics due to the COVID-19 pandemic likely impacted enrollment of vaccinees and data collection.
	TIV-HD/Fluzone HDUK	Number of doses administered was provided to MAH by participating sites (5 hospitals, 1 travel clinic, and 1 pharmacy)	Telephone, email, ADR form by mail and UK Yellow Card Scheme	(−) Disruption to health-seeking behaviour and staffing/routines in clinics due to the COVID-19 pandemic likely impacted enrollment of vaccinees and data collection.(−) Low number of vaccinees
2021/22¹⁹	QIV/VaxigripTetraFinlandQIV-HD/EflueldaGermany	Data collected on vaccination cards and entered into an EDC system	ADR form via an electronic system and telephone	(+) Exposure data well documented and monitored on a real-time basis.(+) Use of an electronic ADR form simplified data collection and management.(+) The electronic system enabled safety concerns to be rapidly processed by local pharmacovigilance staff through automatic notifications once a new ADR was reported.
2022/23²⁰	QIV/VaxigripTetraFinlandQIV-HD/EflueldaGermany	Data collected on vaccination cards and entered into an EDC system	ADR form via an electronic system and telephone	(+) Exposure data well documented and monitored on a real-time basis.(+) Use of an electronic ADR form simplified data collection and management.(+) The electronic system enabled safety concerns to be rapidly processed by local pharmacovigilance staff through automatic notifications once a new ADR was reported.
2023/24²¹	QIV/VaxigripTetraFinlandQIV-HD/EflueldaGermany	Data collected on vaccination cards and entered into an EDC system	ADR form via an electronic system and telephone	(+) Exposure data well documented and monitored on a real-time basis.(+) Use of an electronic ADR form simplified data collection and management.(+) The electronic system enabled safety concerns to be rapidly processed by local pharmacovigilance staff through automatic notifications once a new ADR was reported.

ADR, Adverse drug reaction; EDC, Electronic data capture; HD, High dose; MAH, Marketing Authorization Holder; QIV, Quadrivalent; TIV, Trivalent; UK, United Kingdom.

Safety data collection methods evolved over the seasons. Telephone reporting to Sanofi local PV department was employed in the 2015/16, 2016/17, and 2017/18 seasons. A structured telephone interview was developed to ensure the appropriateness and completeness of data collection when the vaccinees called to report ADRs. In the 2018/19 season, email reporting was introduced, followed by the use of mailed ADR forms (with prepaid envelope) in the 2019/20 season. These three methods of ADR reporting presented limitations due to the magnitude of underreporting and poor quality of information collected.

The transition to a more streamlined process occurred in the 2020/21 season with the implementation of a structured ADR reporting form in an EDC system, which continued to be used until the last season (2023/24). The use of the electronic system facilitated the ADR reporting by the vaccinees, simplified data management, and enhanced accuracy and completeness of ADR reports. Each new ADR report triggered an automatic notification to the Sanofi local PV department, facilitating the seamless integration of data into the Sanofi global PV database and rapid processing of any safety concerns. The Sanofi Pharmacovigilance Database is a validated, secure electronic system designed to collect, store, retrieve, and analyze safety information related to Sanofi products throughout their lifecycle. It serves as the centralized repository for all adverse event reports and safety-related data, enabling systematic monitoring, assessment, and reporting of safety signals in compliance with global regulatory requirements. This approach contributed to a robust and timely safety surveillance system for the vaccines. It is expected that the electronic reporting system favor the reporting of ADR and mitigate the underreporting commonly observed in passive surveillance. This could be reflected in the reporting rates for VaxigripTetra in Finland documented between seasons 2018/19 and 2023/24 (Table 2). However, other factors may impact the reporting rates, including the reactogenicity of the seasonal vaccine formulation, age distribution of vaccinees, and varied reporting behaviors (e.g., HCPs, being the target population of vaccination campaigns and having familiarity with pharmacovigilance processes, are likely more prone to report an ADR they had experienced; elderlies may adhere less to digital reporting tools).^23,24

Table 2.

Vaccinee reporting rates within 7 days after influenza vaccination from season 2015/16 through season 2023/24.

Season	Vaccine	Country	N Vaccinees	Age distributionn (%)	ADRs ⩽ 7 days
Season	Vaccine	Country	N Vaccinees	Age distributionn (%)	n Vaccinees with ADR	n ADRs	Vaccinee RR* (95% CI)
2015/16¹¹	TIV/Vaxigrip	Finland and UK	1012	6 m–5 y: 496 (49.0)6 y–12 y: 111 (11.0)13–17 y: 19 (1.9)18–65 y: 149 (14.7)>65 y: 237 (23.4)	31	110	3.1% (2.0, 4.1)
	TIV/Intanza	UK	1017	60–65 y: 123 (12.1)>65 y: 894 (87.9)	29	99	2.9% (1.8, 3.9)
2016/17¹²	TIV/Vaxigrip	Ireland and UK	962	6 m–5 y: 131 (13.6)6 y–12 y: 191 (19.9)13–17 y: 85 (8.8)18–65 y: 145 (15.1)>65 y: 410 (42.6)	17	59	1.8% (0.9, 2.6)
	TIV/Intanza	UK	1000	⩾60 y: 1000 (100)	21	101	2.1%
2017/18¹³	TIV/Vaxigrip	Ireland and UK	1005	6 m–5 y: 7 (0.7)6 y–12 y: 13 (1.3)13–17 y: 6 (0.6)18–64 y: 362 (32.4)⩾65 y: 653 (65.0)	13	30	1.3% (0.6, 2.0)
	QIV/VaxigripTetra	UK	957	6 y–12 y: 4 (0.4)13–17 y: 6 (0.6)18–64 y: 276 (28.8)⩾65 y: 671 (70.1)	18	39	1.9% (1.0, 2.7)
	TIV/Intanza	UK	979	⩾60 y: 977 (99.8)**	27	71	2.8% (1.7, 3.8)
2018/19¹⁴	TIV/Vaxigrip	Denmark	1000	18–64 y: 205 (20.5)⩾65 y: 795 (79.5)	11	27	1.10% (0.45, 1.75)
	QIV/VaxigripTetra	Finland	996	6 m–5 y: 7 (0.7)6 y–12 y: 10 (1.0)13–17 y: 5 (0.5)18–64 y: 951 (95.5)⩾65 y: 23 (2.3)	28	76	2.81% (1.78, 3.84)
2019/20¹⁵	QIV/VaxigripTetra	Finland	939	6 m–5 y: 1 (0.1)6 y–12 y: 7 (0.7)13–17 y: 9 (1.0)18–64 y: 884 (94.1)⩾65 y: 37 (3.9)Missing: 1 (0.1)	38	117	4.05% (2.79, 5.31)
	TIV-HD/Fluzone	UK	1384	⩾65 y: 1384 (100)	0	0	-
2020/21¹⁶	QIV/VaxigripTetra	Finland	1008	6 y–12 y: 2 (0.2)13–17 y: 4 (0.4)18–64 y: 937 (93.0)⩾65 y: 32 (3.2)Missing: 33 (3.3)	28	79	2.78% (1.85, 3.99)
	TIV-HD/Fluzone	UK	594	⩾65 y: 594 (100)	6	10	1.01% (0.37, 2.19)
2021/22¹⁷	QIV/VaxigripTetra	Finland	1000	6 y–12 y: 4 (0.4)13–17 y: 5 (0.5)18–64 y: 906 (90.6)⩾65 y: 84 (8.4)Missing: 1 (0.1)	49	125	4.90% (3.65, 6.43)
	QIV-HD/Efluelda	Germany	903	⩾65 y: 903 (100)	17	53	1.88% (1.10, 3.00)
2022/23¹⁸	QIV/VaxigripTetra	Finland	1001	13–17 y: 2 (0.2)18–64 y: 971 (97.0)⩾65 y: 28 (2.8)	48	133	4.80% (3.56, 6.31)
	QIV-HD/Efluelda	Germany	1041	⩾65 y: 1041 (100)	6	15	0.58% (0.21, 1.25)
2023/24²¹	QIV/VaxigripTetra	Finland	1003	6 m–5 y: 205 (20.1)6 y–12 y: 38 (3.8)13–17 y: 20 (2.0)18–64 y: 346 (34.5)⩾65 y: 397 (39.6)	81	192	8.08% (6.46, 9.94)
	QIV-HD/Efluelda	Germany	1075	⩾65 y: 1075 (100)	15	46	1.40% (0.78, 2.29)

The vaccinee RR was calculated as the number of vaccinees reporting at least one ADR divided by the total number of vaccinees.

For two vaccinees, age was outside the indicated age range (⩾60 years) for Intanza.

ADR, Adverse drug reaction; CI, confidence interval; HD, high dose; m, month; QIV, Quadrivalent; RR, reporting rate; TIV, trivalent; UK, United Kingdom; y, year.

Operational challenges

The implementation of the EPSS faced some operational challenges over the years, starting with the country selection process, which was influenced by the availability of the vaccine brand within the EU member states, a factor directly affected by the existing tender system. The unpredictability of this process means that a country included in one study is not guaranteed to be part of subsequent studies, posing challenges for season-to-season comparisons, especially when national recommendations, populations, and healthcare behaviors differ. Additionally, late tenders can affect study implementation due to delays in site selection and ethics committee submissions.

Site selection was often challenging as there were difficulties in finding facilities where HCPs were willing to participate, vaccinees could be rapidly enrolled, and all age groups could be adequately represented according to each vaccine brand’s indication. Achieving adequate representation of children was particularly difficult because they were often eligible for free vaccination through public healthcare programs, making them less likely to visit the private clinics participating in the EPSS. Additionally, in some countries, a nasal spray formulation of the live attenuated influenza vaccine was the preferred option for children aged 24 months to 6 years. Each season aimed to recruit 1000 vaccinees per vaccine brand to allow the detection of common ADRs. However, during the 4 to 6-week recruitment period, defined a priori to promptly identify any safety concerns early in the season, the target sample size was not reached in some years (Table 2).

Despite the challenge of country and site selection, the implementation of the EPSS was facilitated by existing collaborations in certain seasons and countries (e.g., Germany and Finland), allowing for comparison of reporting rates across multiple seasons within the same country and vaccine brand.

UK-specific challenges

The EPSS implemented in the UK during the 2019/20 and 2020/21 seasons adopted distinct data collection strategies. In the 2019/20 season, the EPSS was implemented in hospital settings, and vaccines were dispensed by the hospital pharmacy without distributing VCs to recipients. This hampered the recording of exposure information and the linking of vaccine administration to potential ADRs. Safety data were collected exclusively through the UK Yellow Card Scheme, as per MHRA recommendations. Similarly, in the 2020/21 season, challenges persisted in exposure data collection as most participating sites were also in hospitals. ADR reporting via UK Yellow Card Scheme was supplemented by telephone, email, and mail reporting. Moreover, the impact of the COVID-19 pandemic on healthcare systems added complexity to the EPSS implementation.^25–27 Consequently, the enhanced aspect of the surveillance was not fully guaranteed in both seasons in the UK.

In both seasons in the UK, the EPSS targeted individuals ⩾65 years old as per label indication of the high-dose influenza vaccine. The predominance of hospital settings likely resulted in an over-representation of patients with cardiovascular, respiratory, and other comorbidities in our surveillance population compared to a broader elderly population receiving influenza vaccines in community settings in the UK.

Future perspectives for seasonal influenza vaccine safety surveillance

Nationwide safety surveillance outside Europe

While Sanofi’s EPSS approach provides valuable safety data within specific European countries and populations, countries outside Europe adopt unified nationwide safety surveillance systems for monitoring seasonal influenza vaccine safety. A unified, nationwide safety surveillance system with harmonized and comprehensive safety data collection offers better comparability of adverse event rates across influenza seasons and enhances quality of reporting. Additionally, the use of a real-time approach to data collection is crucial for monitoring adverse events during peak immunization periods. Such a system may booster public confidence through transparent and coordinated monitoring. In Australia and the United States (US), safety surveillance systems have been established to assess vaccine safety and have been used annually for seasonal influenza vaccines.

AusVaxSafety is as a nationwide active vaccine safety surveillance system in Australia. Initially designed for influenza vaccine safety monitoring in children aged 6 months to 4 years in 2014, the system has expanded its scope to monitor various vaccines included in the Australian immunization program. This collaborative effort involves the Australian Government Department of Health, the National Centre for Immunisation Research and Surveillance, and state and territory health departments. Using an short message service (SMS)-based system, AusVaxSafety ensures real-time reporting of adverse events by sending surveys to vaccinees shortly after vaccination via a cell phone text message or email. This active approach of systematically soliciting responses from vaccinees distinguishes it from enhanced passive surveillance, which relies on spontaneous reporting.²⁸ In addition, since 2022, a predictive analysis has been implemented into the influenza vaccine signal detection process. A safety signal is flagged when the observed number of events exceeds the 99th percentile of the predicted distribution.²⁹ The results of the safety surveillance of seasonal influenza vaccines are publicly available each season in the AusVaxSafety website and detailed in some publications.^28,30

In the United States, the Centers for Disease Control and Prevention (CDC) has established the Vaccine Safety Datalink (VSD) to evaluate postmarketing vaccine safety. As a collaboration between CDC and several large healthcare organizations, VSD uses electronic health data to monitor and assess the safety of vaccines and has a capacity to detect rare and serious adverse events following immunization in near real-time.³¹ For seasonal influenza vaccines, VSD analyzes data on a weekly basis using the maximized sequential probability ratio test (MaxSPRT) method. This approach ensures that any important safety concern can be promptly detected and communicated to the public.³² In addition to VSD, the FDA’s Center for Biologics Evaluation and Research manages two other postlicensure safety monitoring systems. The Postlicensure Rapid Immunization Safety Monitoring system, part of the Sentinel Initiative, uses large healthcare databases to conduct active surveillance of vaccine safety.^33,34 The Biologics Effectiveness and Safety System similarly utilizes electronic health records and insurance claims data to monitor biologics safety, including vaccines.³⁵

Opportunities for European safety surveillance

Some of the challenges highlighted in this article were also encountered by other MAHs, indicating systemic issues that necessitate broad collaboration and strategic oversight.³⁶ This recognition underscores the imperative for coordinated efforts among EMA, national regulatory and public health agencies, and vaccine manufacturers to enhance safety surveillance in Europe by sharing data, expertise, and resources. An effective Europe-wide surveillance system should distinguish between vaccine brands and accommodate various vaccine providers, ensuring streamlined procedures, obtaining safety data from a large population, and representing all age groups covered by indications. A unified system allows consistent safety surveillance implementation, enabling comparability of ADR rates across vaccine brands and influenza seasons, fostering vaccinee trust and improving reporting rates. Ultimately, that contributes to a more robust and reliable safety surveillance framework. Such a system could be particularly valuable in monitoring the safety of vaccines during pandemics or large-scale vaccination campaigns. Furthermore, advancing such a surveillance system could incorporate advanced technologies and methodologies, including real-time data analytics, artificial intelligence, and machine learning, to improve the speed and accuracy of safety signal detection. These innovations could provide a more dynamic and responsive surveillance framework, allowing for quicker interventions and increased public safety confidence.

Expectations for an EMA guidance update involve not only the anticipation of new regulatory requirements but also open potential opportunities for collaboration and knowledge exchange among vaccine manufacturers. By sharing experiences and lessons learned, this collaboration can lead to the proposal and development of more efficient methods or systems for rapid safety signal identification compared to the current proposed enhanced surveillance.

Limitations

This review presents the experience of a single MAH, which may not fully represent the challenges and perspectives of other vaccine manufacturers implementing enhanced safety surveillance in Europe. In addition, our experience is limited to the specific countries where our EPSS studies were conducted (Finland, UK, Republic of Ireland, Denmark, and Germany), potentially missing important contextual factors from other European regions. Despite these limitations, this review provides valuable insights into the practical implementation of EPSS for seasonal influenza vaccines in Europe.

Conclusion

The landscape of seasonal influenza vaccine safety surveillance in Europe has undergone significant evolution since 2015, when the EMA introduced enhanced safety surveillance requirements. Sanofi has adapted to these changes and implemented EPSS over nine influenza seasons. In the recent seasons, Sanofi demonstrated innovative methods for data collection using electronic reporting systems that have improved data quality and enabled near real-time safety monitoring. While operational challenges persist, particularly in achieving cross-country consistency, the potential for a unified Europe-wide safety surveillance system is evident. As EMA prepares to refine its recommendations in 2025, the future of vaccine safety monitoring hinges on collaborative efforts among regulatory bodies, public health agencies, and vaccine manufacturers. This ongoing evolution and cooperation promise to strengthen overall vaccine safety surveillance, ultimately benefiting public health across Europe.

Supplemental Material

sj-docx-1-taw-10.1177_20420986261416017 – Supplemental material for Challenges and future perspectives of enhanced passive safety surveillance of influenza vaccines in Europe

Supplemental material, sj-docx-1-taw-10.1177_20420986261416017 for Challenges and future perspectives of enhanced passive safety surveillance of influenza vaccines in Europe by Marina Amaral de Avila Machado, Sonja Gandhi-Banga, Laurence Serradell, Sophie Gallo, Sophie Wagué, Tamala Mallett Moore and Alena Khromava in Therapeutic Advances in Drug Safety

Footnotes

Acknowledgements

SGB was an employee of Sanofi during the manuscript development and currently holds an affiliation with Alexion, AstraZeneca Rare Disease, Mississauga, Canada.

Declarations

ORCID iDs

Marina Amaral de Avila Machado

Sonja Gandhi-Banga

Laurence Serradell

Sophie Gallo

Sophie Wagué

Tamala Mallett Moore

Alena Khromava

Supplemental material

Supplemental material for this article is available online.

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