Comparative safety evaluation of pentavalent (DTaP-IPV-Hib) and hexavalent (DTaP-IPV-Hib-HepB) vaccines in infants: a real-world analysis based on VAERS.

Background: Combination vaccines simplify immunization schedules and improve compliance, making them a global priority in pediatric immunization strategies. The DTaP-IPV-Hib pentavalent vaccine has been widely adopted, and with the incorporation of the hepatitis B vaccine (HepB), the DTaP-IPV-Hib-HepB hexavalent vaccine was developed. However, whether the addition of antigens in the hexavalent formulation is linked to differences in the reporting of adverse events following immunization (AEFIs) remains a matter of ongoing debate. Objective: This study aims to compare the safety profiles and differences in AEFIs between the pentavalent vaccine and the hexavalent vaccine in infants aged 6 weeks to 2 years, based on real-world data from the U.S. Vaccine Adverse Event Reporting System (VAERS). The study also seeks to identify potential safety signals and evaluate correlates of death classification among reports. Methods: AEFIs reported to the VAERS from 2018 to 2024 were analyzed. Four disproportionality analysis methods-including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-Item Gamma Poisson Shrinker (MGPS)-were used to identify potential safety signals. A multivariable logistic regression model was employed to examine factors associated with reports classified as death. Results: A total of 4,980 AEFI reports were included (3,259 for the pentavalent vaccine and 1,720 for the hexavalent vaccine). Reports following hexavalent vaccination more frequently involved serious AEFIs-particularly hospitalization and life-threatening events-than reports following pentavalent vaccination, especially among infants aged 6 weeks to 4 months, in whom apnea and cyanosis were more frequently reported. Disproportionality analysis showed that reports for the hexavalent vaccine generated stronger disproportionality signals in multiple systems, including nervous system disorders (ROR = 1.95; IC025 = 0.70), vascular disorders (ROR = 2.89; IC025 = 1.17), cardiac disorders (ROR = 1.92; IC025 = 0.45), and respiratory disorders (ROR = 1.33; IC025 = 0.19). In the multivariable model, increasing age and female sex were associated with lower odds of reports being classified as death. Co-administration with other vaccines was associated with higher odds of death classification in the pentavalent subset, with no clear association observed in the hexavalent subset. Conclusions: While reports for both vaccines were generally consistent with known safety profiles, those following hexavalent vaccination showed stronger disproportionality signals in younger infants. These findings are hypothesis-generating and highlight the importance of targeted post-vaccination monitoring; they do not establish causality.