Enhanced safety surveillance of GSK's quadrivalent seasonal influenza vaccine in Germany and Spain (2021/2022 season) using an electronic patient‐reported outcome system for vaccine safety remote monitoring

**Background:** Seasonal influenza epidemics are managed through annual vaccination in the European Union. Because circulating virus strains vary unpredictably, vaccines are reformulated each year and require rapid, continuous safety monitoring at the start of each season per European Medicines Agency guidelines. This enhanced safety surveillance (ESS) study assessed GSK's inactivated quadrivalent seasonal influenza vaccine (IIV4) during the 2021/2022 season, which coincided with the COVID-19 pandemic.

**Methods:** This prospective ESS study was conducted between October 1, 2021 and January 7, 2022 in Germany and Spain. The study aimed to enroll approximately 1000 participants from five healthcare providers. Participants included all age groups for which IIV4 is indicated (from 6 months of age), with recruitment targeting adults aged 18 years and older in Germany and participants aged over 6 months in Spain. A second dose was administered only to children aged <9 years who had not previously been vaccinated against influenza. Safety data were collected using an electronic Case Report Form completed by investigators and participants via an electronic Patient Reported Outcome (e-PRO) web-based portal or with assistance from a call center. The primary objective was to estimate the cumulative percentage of participants reporting pre-specified adverse events of interest (AEIs) and any other AEs within 7 days of vaccination. All analyses were descriptive, with 95% confidence intervals accounting for clustering effects of centers.

**Key Results:** Of 979 enrolled vaccinees, 977 provided valid consent (422 adults in Germany, 555 participants in Spain including 324 children and 231 adults). The Safety Set included 737 participants (315 in Germany, 422 in Spain). Median age was 49 years in Germany and 9 years in Spain; 38.1% were aged <18 years, 56.9% were 18-65 years, and 5.0% were >65 years. Most participants (96.2%) were Caucasian, and 57.0% were not considered at risk for influenza-associated morbidity. After Dose 1, 332 participants (45.1%) reported at least one AE, with 52.4% in Germany and 39.6% in Spain. The most common AEs after Dose 1 were injection site pain (31.8%), fatigue (11.4%), headache (9.8%), injection site swelling (8.7%), and injection site erythema (5.0%). Severity was mild in 23.1%, moderate in 17.1%, and severe in 4.9% of participants. After Dose 2 (administered to 19 children), 5 participants (26.3%) reported AEs, most commonly injection site pain (15.8%), rhinorrhea (15.8%), fatigue (10.5%), decreased appetite (10.5%), and irritability (5.3%). No deaths occurred, and no serious AEs deemed related to the vaccine were reported. No cases of febrile convulsion, anaphylactic reaction, Bell's palsy, or Guillain-Barre syndrome were observed. The electronic ADR completion rate was 75.4% following Dose 1 and 100% following Dose 2.

**Clinical Implications:** This study confirms the established safety profile of GSK's IIV4 across all age groups, with no new or unexpected safety signals detected. The adverse event types and frequencies were consistent with the vaccine's Summary of Product Characteristics. The successful implementation of an electronic safety reporting system (e-PRO web portal and call center) provides a viable alternative for future vaccine safety surveillance, particularly when site visits are not feasible (e.g., during pandemic lockdowns). The response rates of 75.4% after Dose 1 and 100% after Dose 2 demonstrate acceptable feasibility, though lower than traditional paper-based methods. The study also captured co-administration data (11.2% for Dose 1) and COVID-19 history, finding no interference with the IIV4 safety profile.