Safety of nirsevimab in children aged 0–24 months: Analysis based on EudraVigilance data (2023–2025)

ABSTRACT

Respiratory syncytial virus (RSV) is a cause of severe lower respiratory tract infections in infants, and it is associated with substantial morbidity, including hospitalization and death. After European Medicine Agency approval of nirsevimab, a monoclonal antibody against RSV, immunization campaigns have been implemented in several European Union countries for administration to children as preventive intervention against severe RSV disease during RSV epidemic season. Monitoring its safety in routine healthcare practice is also important. We described suspected adverse drug reactions (ADRs) following nirsevimab administration in children aged 0–24 months, reported in the EudraVigilance system between 2023 and 2025. There were 1,923 ADRs, corresponding to 808 cases. By System Organ Class, ADRs mainly included general disorders and administration site conditions, which include nonspecific systemic manifestations and administration-site reactions that cannot be readily assigned to a single organ system (28.4%), infections and infestations (23.3%), respiratory, thoracic, and mediastinal disorders (12.2%); by Preferred Terms most frequent were drug ineffective (12.6%), and RSV bronchiolitis (9.6%). In addition, pyrexia, rash, and injection site reactions were also common. This study offered systematic characterization of ADRs following administration of nirsevimab. It found that the reported ADRs are consistent with the safety results from pre- and real-world safety studies. Our study can support the continue monitoring of the real-world safety and guide the planning of analytical observational studies on the safety profile of nirsevimab.

Introduction

Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract infections (LRTIs) in infants worldwide. It is associated with hospitalization and LTRI long-term respiratory sequelae and death.¹ Recognized risk factors for respiratory RSV‑related infection and hospitalization are young age, preterm birth, underlying chronic diseases (particularly congenital heart defects and chronic lung diseases), and, having older siblings younger than 4 y.² Recently, research has also found that prematurity, being born small for gestational age, multiple birth, and having underlying comorbidities are the factors most strongly associated with severe RSV disease outcomes.³ According to global burden estimates, infants younger than 6 months have the highest risk of RSV LRTI, representing nearly half of RSV hospitalizations. The estimated community incidence is higher in low-income countries compared with high-income countries, while the hospital incidence is lower, suggesting lower access to health services.¹

RSV typically follows a global seasonal pattern with epidemic wave starting from the Southern hemisphere between March and June, reaching the Northern hemisphere between September and December. It circulates between October and May in some of the European Countries.⁴

Nirsevimab is a long-acting monoclonal antibody that neutralizes RSV by binding the prefusion conformation of the F glycoprotein, thereby preventing viral fusion with host cells and limiting cell-to-cell spread. A key innovation of nirsevimab is the introduction of three amino acid substitutions in the Fc region, which markedly prolongs its half-life and antibody persistence in vivo.⁵ Serological studies showed that a single intramuscular dose maintains high neutralizing antibody (nAb) titers throughout the RSV season, providing sustained protection that has also been confirmed by real-world effectiveness data.⁶

Nirsevimab was approved by the European Medicines Agency (EMA) on 31 October 2022.⁷ It is now available in the European Union (EU) for administration to newborns and infants as a preventive intervention against severe RSV disease during RSV epidemic season. Following marketing authorization, some EU countries have implemented prophylaxis with nirsevimab and introduced in their immunization routinely programme for neonates and children.

World Health Organization recommends that all countries introduce maternal RSV vaccination and/or nirsevimab “consider factors such as cost, cost-effectiveness, financing, supply, anticipated coverage and feasibility of implementation within the existing health system.”⁸ Depending on the geographical location of the country and the seasonality of RSV circulation, two approaches for nirsevimab administration can be considered: a year-round approach, in which nirsevimab is administered at birth, and a seasonal approach, in which it is administered to older infants before entering their first RSV season. A dose of long-acting monoclonal antibody can be considered for infants and children aged <2 y who are at increased risk for severe RSV disease entering their second RSV season.

In a pre-marketing phase 2b randomized controlled trial (RCT),⁹ a single injection of nirsevimab showed an efficacy of 70.1% (95% CI, 52.3–81.2) against medically attended RSV-associated LRTIs and 78% (95% CI, 51.9–90.3) against hospitalization for RSV-associated lower respiratory tract infection (LRTIs) in healthy preterm infants (n = 1453; gestational age ≥29 to <35 weeks).

Additionally, a phase 3 RCT¹⁰ showed an efficacy of 74.5% (95% CI, 49.6–87.1) against medically attended RSV-associated LRTIs, 62.1% (95% CI, 8.6–86.8) against hospitalization for RSV-associated LRTIs in healthy term and late preterm infants (n = 1,490; gestational age ≥35 weeks). A post-marketing study conducted in Spain¹¹ confirmed substantial effectiveness in preventing RSV-LRTI hospitalization in 15,676 infants younger than 9 months (84.4%; 95% CI 76.8–90.0). A recent systematic review and meta-analyses confirmed effectiveness of nirsevimab in preventing RSV- related outcomes in real‑world condition conducted in five countries (Spain, France, USA, Italy, Luxembourg) confirmed effectiveness of nirsevimab during the first season of immunization programme (2023–2024).¹² The pooled analysis of these studies revealed that nirsevimab in children aged 0–12 months substantially decreased the risk of RSV-related hospitalization (OR 0.17, 95% CI 0.12–0.23), RSV-related ICU admissions (OR 0.19, 95% CI 0.12–0.29) and of LRTI (OR 0.25, 95% CI 0.19–0.33). The safety profile emerged as favorable from pre-marketing trials and the suspected adverse drug reactions (ADRs) included in Summary of Product Characteristics¹³ were non-serious such as pyrexia, rash, rash maculo-papular, rash macular, and injection site reactions.

However, it is essential to continue monitoring the safety of nirsevimab through both passive and active pharmacovigilance initiatives, since questions may arise when medicines are used on a large scale. These initiatives are of particular importance for the identification of rare or long-term ADRs that might not be observed in pre-marketing clinical trials, which are limited in number of participants and follow‑up duration and conducted in selective group of population.

The objective of this study is to collect and describe suspected adverse drug reactions (ADRs) following nirsevimab administration in children aged 0–24 months and spontaneously reported in the EudraVigilance (European Union Drug Regulating Authorities Pharmacovigilance) system.

Materials and methods

Suspected ADRs were systematically identified in the EudraVigilance system from 1 January 2023 to 1 December 2025. EudraVigilance is the EMA’s centralized pharmacovigilance and publicly available database, which manages, analyses and collects suspected adverse reactions to medicines authorized or under clinical investigation in the European Economic Area (EEA); EudraVigilance collects cases that are reported spontaneously from healthcare professionals and consumers.¹⁴

Data files were exported from EudraVigilance in CSV format for each year of the study (2023, 2024, 2025), filtered to include only cases reported by EU countries, and merged into a single dataset. We performed a descriptive analysis of the ADR reports stratified by sex, age group (0–1 months, 2–24 months), reporter type (healthcare professionals or non-healthcare professionals, including patient-reported cases), year of reporting (2023, 2024, 2025), seriousness (serious and not serious), and categorized using Medical Dictionary for Regulatory Activities at System Organ Class (SOC) and Preferred Terms level (PT). Categorical variables were summarized as absolute numbers and percentages.

The temporal pattern of ADRs was assessed through monthly distribution from October 2023 to November 2025 to identify temporal trends and seasonal variations. In addition, for each year in the study, ADRs were stratified by SOC and seriousness.

STATA® Software version 16 was used for data processing and analyses.

Results

Table 1 shows the number of cases with at least one ADR and the total number of ADRs distributed by year, sex, age, reporter type, seriousness, and SOC. ADRs were also described by PT, and those more than 50 are shown in Table 1. Over the study period, a total of 808 cases with at least one nirsevimab suspected ADR were reported in the EudraVigilance database, corresponding to 1,923 ADRs (mean 2.4 per case; Table 1). Cases and suspected ADRs increased year by year reaching, respectively, the number of 398 and 1036 in 2025. Children aged 2–24 months (n = 1,172; 60.9%) and males (n = 1,056; 54.9%) accounted for a larger number of ADRs than those aged 0–1 months.

Table 1.

Distribution of cases and ADRs following nirsevimab in EudraVigilance database (2023–2025).

	N. cases (%)	N. ADRs (%)
All Reports	808	1,923
Year of received
2023	110 (13.6%)	217 (11.3%)
2024	300 (37.1%)	670 (34.8%)
2025	398 (49.3%)	1036 (53.9%)
Age group
Newborns 0–1-months	342 (42.3%)	751 (39.1%)
Serious*	232 (67.8%)	557 (74.2%)
Children 2–24 months	466 (57.7%)	1,172 (60.9%)
Serious*	239 (51.3%)	701 (59.8%)
Sex
Males	431 (53.3%)	1,056 (54.9%)
Females	335 (41.5%)	781 (40.6%)
Not specified	42 (5.2%)	86 (4.5%)
Seriousness
Serious	471 (58.3%)	1,097 (57.0%)
Other outcome/Other medically important condition	112 (13.9%)	197 (10.2)
Caused/Prolonged hospitalization	299 (37.0%)	776 (40.4%)
Disability	0	0
Life threatening	47 (5.8%)	104 (5.4%)
Results in death	13 (1.6%)	20 (1.0%)
Not serious	337 (41.7%)	826 (43.0%)
Reporter
Health professionals	717 (88.7%)	1,668 (86.7%)
Not healthcare professionals	91 (11.3%)	255 (13.3%)
SOC and PTs (N > 50)
General disorders and administration site conditions		547 (28.4%)
Drug ineffective		242 (12.6%)
Pyrexia		114 (5.9%)
Infections and infestations		448 (23.3%)
Respiratory Syncytial Virus Bronchiolitis		185 (9.6%)
Bronchiolitis		99 (5.1%)
Respiratory Syncytial Virus Infection		59 (3.1%)
Respiratory Syncytial Virus Test positive		54 (2.8%)
Respiratory, thoracic and mediastinal disorders		234 (12.2%)
Skin and subcutaneous tissue disorders		173 (9.0%)
Rash		52 (2.7%)
Investigations		101 (5.3%)
Gastrointestinal disorders		91 (4.7%)
Nervous system disorders		76 (4.0%)
Surgical and medical procedures		57 (3.0%)
Metabolism and nutrition disorders		46 (2.4%)
Injury, poisoning and procedural complications		28 (1.5%)
Vascular disorders		23 (1.2%)
Psychiatric disorder		21 (1.1%)
Cardiac disorder		18 (0.9%)
Blood and lymphatic system disorders		17 (0.9%)
Eye disorders		13 (0.7%)
Immune system disorders		7 (0.4%)
Musculoskeletal and connective tissue disorders		6 (0.3%)
Social circumstances		5 (0.3%)
Renal and urinary disorders		4 (0.2%)
Pregnancy, puerperium, perinatal conditions		3 (0.2%)
Ear and labyrinth disorders		2 (0.1%)
Hepatobiliary disorders		1 (0.1%)
Not specified		2 (0.1%)

ADR: Adverse drug Reaction; N.: Number; SOC: System Organ Class; PTs: Preferred Terms; *Percentages are calculated within each age group.

Majority of the ADRs were reported by health professionals (n = 1,688; 86.7%). By SOCs, the reported ADRs were predominantly categorized as general disorders and administration site conditions (n = 547; 28.4%), infections and infestations (n = 448; 23.3%) and respiratory, thoracic and mediastinal disorders (n = 234; 12.2%). The most frequent PTs (n > 50) were drug ineffective (n = 242; 12.6%), RSV bronchiolitis (n = 185; 9.6%), pyrexia (n = 114; 5.9%), bronchiolitis (n = 99; 5.1%), RSV infections (n = 59; 3.1%), RSV test positive (n = 54; 2.8%), and rash (n = 52; 2.7%). Among the ADRs listed in Summary of Product Characteristics,¹³ besides pyrexia, we identified different types of rashes (n = 52 rash, n = 11 rash maculo-papular, n = 7 rash macular) as well as of injection site reactions (n = 15) (data not shown). Among the events mentioned as not important in the EU Risk Management Plan of nirsevimab,¹⁵ we identified 4 cases of thrombocytopenia, 2 cases of anaphylactic reactions and 1 case of anaphylactic shock (the more severe anaphylactic manifestation) (Supplementary material, Table S1). Of the 4 cases of thrombocytopenia, 2 cases resolved and 1 case was resolving at the time of reporting, while the one unresolved case had received concomitant vaccinations (hexavalent, meningococcal, and pneumococcal vaccine) and presented other serious ADRs. The case of shock was resolving, while of the cases of anaphylactic reactions, one was resolving and the other was of unknown outcome. No concomitant medications were administered in these anaphylactic cases.

There were 1,097 serious ADRs (57.0%) corresponding to 471 serious cases (58.3%), of which 13 (1.6%) were fatal. Newborns aged 0–1 months experienced a higher proportion of serious ADRs than those aged 2–24 months, featuring 557 (74.2%) serious ADRs with seven fatalities (data not shown).

Of the 13 fatal cases,10 were females and seven occurred in infants aged 0–1 months. The reported PTs were: Sudden Death syndrome in six cases (including one case with also reported drug ineffective and one with RSV bronchiolitis, autonomic nervous system imbalance and cardiorespiratory arrest); catarrh with multiorgan disfunction syndrome and gastroenteritis in three cases; influenza with bronchiolitis and cardiac disorder in one case; cardiorespiratory arrest in two cases and metabolic acidosis in one case.

In Figure 1, it is apparent a growing annual trend of the ADR distribution. Additionally, a seasonal trend emerged each year, showing an increase during autumn and winter. Likewise, subdivision of ADRs by SOC shows a progressive increase over time within each SOC category (Figure 2).

Figure 1.

Distribution of ADRs following nirsevimab in EudraVigilance database by years and months (2023–2025).

N.: Number; Jan: January; Feb: February; Mar: March; Apr: April; Jun: June; Jul: July; Aug: August; Sep: September; Oct: October; Nov: November; Dec: December.

Data extraction from EudraVigilance for 2023 identified reported ADRs from October 2023 onwards, corresponding to the beginning of real-world availability and use of the drug in Europe.

Figure 2.

Distribution of ADRs following nirsevimab in EudraVigilance database by SOC, seriousness, and years (2023-2025).

N.: Number.

Discussion

There were 1,923 suspected ADRs following nirsevimab reported in EudraVigilance database in EU Countries from January 2023 to December 2025.

The SOCs with the highest proportions of ADRs, representing approximately the 65% of the reported ADRs, were general disorders and administration site conditions, infections and infestations and respiratory, thoracic, and mediastinal disorders. Within these SOCs, the most frequent reported ADRs were drug ineffectiveness, RSV bronchiolitis, RSV infections, and RSV test positive, representing about 50% of the serious ADRs. These reactions might be, at least in part, attributed to the preventive ineffectiveness of the product. It is an interpretation that might be compatible with seasonal growing trend of the ADRs observed in autumn and winter that seems to be concomitant with the widespread use of the product during immunization campaigns and the seasonal pattern of RSV circulation.

The other types of “infections and infestations” seem to be consistent with common seasonal respiratory infections observed in the pediatric population.

Furthermore, the annual rise of the ADRs during the 3‑y study period might reflect the increase of immunization coverage due to the possible intensified effort in strengthening nirsevimab immunization program in EU countries. Also, as for a newly marketed drug, the increased ADRs by year might have been influenced by the enhanced awareness among healthcare professionals and the public.

We also found that children aged 2–24 months accounted for the largest number of reported ADRs. We can speculate that difference observed in the frequency of ADRs between the two age groups reflects the largest number of children aged 2–24 months who received nirsevimab in some European countries (i.e. Spain, Italy, and France) with similar immunization strategies.

The higher proportion of serious ADRs among newborns aged 0–1 months is unlikely to reflect differential reporting or classification bias, as ADR seriousness is determined according to standardized objective criteria. Although the category “other medically important conditions” requires some clinical judgment, it is restricted to medically significant events that may place the patient at risk or require intervention to prevent death or hospitalization. Our results are consistent with the safety results from pre^9,10 and post-marketing studies.^16,17 The pre-marketing Harmonie trial¹⁸ reported that the highest proportion of medically attended adverse events (AEs) belonged to the SOC category Infections and infestations (21.5% nirsevimab vs. 19.9% control group) followed by the far less common AEs (<5%) classified as Respiratory, thoracic, and mediastinal disorders, Gastrointestinal disorders, and General disorders.

With regard to pharmacovigilance studies, Estrella-Porter et al.¹⁶ found that, during the first year of roll out of nirsevimab immunization campaign in Spain, among 141 spontaneously reported ADRs, the highest proportion were classified in General disorders (27.0%), Infections and infestations (18.4%), Skin and subcutaneous tissue disorders (17.7%), manly driven by rash (8.5%), drug ineffective (7.1%), pyrexia (7.1%) and respiratory syncytial virus (6.4%).

Consolati et al.¹⁷ reported adverse events that mostly included fever (6.5%) and local reactions at the injection site (4%) in 369 newborns following nirsevimab prophylaxis in Valle d’Aosta Italian region. Unlike our study, Estrella-Porter¹⁶ and Consolati¹⁷ did not report cases of thrombocytopenia, anaphylactic reactions or anaphylactic shock.

This descriptive study has limitations inherent to the nature of the passive spontaneous surveillance systems, including underreporting of ADRs and missing information. Furthermore, confounding factors such as comorbidities and concomitant medications preclude establishing a causal relationship between nirsevimab and the suspected ADRs.

Given the intrinsic limitations of spontaneous reporting systems such as EudraVigilance, particularly underreporting, reporting bias, and the lack of denominator data, our study was intentionally designed as a descriptive analysis, in line with study’s objective and consistently with previously published pharmacovigilance studies on medical products based on the same data source.¹⁹ In this context, descriptive analyses of reported ADRs represent the fundamental approach for characterizing safety profiles.

Including data from a single pharmacovigilance database might also limit the generalizability of our findings. However, we considered that focusing on EudraVigilance data would provide a more comprehensive and reliable picture of potential post-marketing adverse events compared with other databases, as nirsevimab was first approved in Europe in October 2022 and has therefore been routinely and consistently monitored within this system. In addition, in EU, nirsevimab is under additional monitoring, meaning that it is monitored even more intensively than other medicines: “Additional monitoring aims to enhance reporting of suspected adverse drug reactions for medicines for which the clinical evidence base is less well developed. The main goals are to collect information as early as possible to further inform the safe and effective use of these medicines and their benefit-risk profile when used in everyday medical practice.”²⁰

Furthermore, we did not include, for example, FAERS because in US, during the 2023–24 RSV season, the immunization campaign was limited by shortage of nirsevimab and restricted to infants with high-risk diseases outcome.

Notwithstanding these limitations, this analysis provides a systematic and comprehensive characterization of ADRs following administration of nirsevimab in the largest database available. These findings can be used to continue monitoring the real-world safety and might guide the planning and conducting of analytical observational studies that are still needed to answer research questions on the safety profile of nirsevimab.

Biography

Cristina Morciano has a Master’s degree in Biological Sciences and a Postgraduate Diploma in Epidemiology at the London School of Hygiene and Tropical Medicine, University of London. She works as a senior researcher at the National Centre of Drug Research and Evaluation at Italian National Institute of Health, unit of Pharmacovigilance and Pharmacoepidemiology, in Rome. Her research interests span from pharmacovigilance/pharmacoepidemiology, with a particular focus on the effectiveness and safety of vaccines, to ethics and research integrity.

Funding Statement

The authors reported there is no funding associated with the work featured in this article.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data will be made available on reasonable request.

Supplemental material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/21645515.2026.2739001