Post-marketing Safety Profile of Dengue Vaccines CYD-TDV and TAK-003: Analysis of Adverse Event Reports from a European Database

Viviana Maria Gianguzzo¹Michelangelo Rottura²Federica Maria Sacco²Matthew Gavino Donadu³Giuseppina Sanna⁴Natasha Irrera²Egidio Imbalzano²Vincenzo Arcoraci²Giuseppinella Melita⁵Ylenia Marino⁶Sara Manti^5*Giovanni Pallio⁶

• ¹Universita degli Studi di Messina Dipartimento di Scienze Chimiche Biologiche Farmaceutiche ed Ambientali, Messina, Italy
• ²Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
• ³Department of Medicine, Surgery and Pharmacy, Scuola di Specializzazione in Farmacia Ospedaliera, University of Sassari, Sassari, Italy
• ⁴Universita degli Studi di Cagliari Dipartimento di Scienze Biomediche, Cagliari, Italy
• ⁵Department of Human Pathology of Adult and Childhood Gaetano Barresi, University of Messina, Messina, Italy
• ⁶Universita degli Studi di Messina Dipartimento di Scienze biomediche odontoiatriche e delle immagini morfologiche e funzionali, Messina, Italy

Introduction: Dengue is one of the major global public health burden, particularly in endemic regions. CYD-TDV and TAK-003 are the currently licensed live attenuated tetravalent dengue vaccines, differing in serostatus indication, age range, and immunogenic design. While efficacy has been demonstrated in clinical trials, post-marketing safety data are still limited, supporting the need for real-world pharmacovigilance analyses. Objective: This study characterize adverse reactions associated with CYD-TDV and TAK-003 reported in the European pharmacovigilance database and to compare their post-marketing safety profiles. Methods: A retrospective pharmacovigilance study was conducted using the EudraVigilance database. Individual Case Safety Reports (ICSRs) listing CYD-TDV or TAK-003 as suspected products were retrieved. Adverse drug reactions were coded using MedDRA® version 28.1 and classified by seriousness and outcome. Disproportionality analyses were performed using Reporting Odds Ratios (RORs) with 95% confidence intervals at the System Organ Class (SOCs) and Preferred Terms (PTs) levels. Sensitivity analyses included grouping clinically related PTs and restricting analyses to serious cases. Vaccine groups were compared using chi-square tests. Results: A total of 2,288 ICSRs were identified, including 1,768 (77.3%) related to TAK-003 and 520 (22.7%) to CYD-TDV. TAK-003-related reports mainly involved adults (49.8%) and females (57.9%). Although most ICSRs were classified as serious, serious reports were more frequent for CYD-TDV than for TAK-003 (81.1% vs 76.4%; p=0.04). Fatal outcomes were also more commonly reported for CYD-TDV (50.8% vs 0.6%; p<0.01). At the SOC level, TAK-003 showed lower disproportional reporting than CYD-TDV for infections and infestations (ROR=0.07; 95% CI=0.056– 0.089), gastrointestinal disorders (ROR=0.22; 95%CI=0.18–0.27), general disorders and administration site conditions (ROR=0.29; 95%CI=0.23–0.36), nervous system disorders (ROR=0.42; 95%CI=0.34–0.51), cardiac disorders (ROR=0.35; 95%CI=0.23–0.51), and hepatobiliary disorders (ROR=0.09; 95%CI=0.04–0.19). Higher reporting for TAK-003 was observed for skin and subcutaneous tissue disorders (ROR=1.98; 95%CI=1.59–2.48). Conclusions: This real-world pharmacovigilance study suggests that TAK-003 is predominantly associated with non-serious, reactogenic adverse reactions, whereas CYD-TDV reports more frequently involve serious outcomes, likely reflecting differences in indications and epidemiological contexts. Continued post-marketing surveillance remains essential for both vaccines.