Vaccination is one of the most effective public health interventions for reducing the incidence and mortality of infectious diseases in infants and young children (Nandi and Shet, 2020). To enhance vaccination efficiency, simplify immunization schedules, and improve compliance and coverage, the development and implementation of combination vaccines has become a key focus of global immunization strategies (Elliman and Bedford, 2003; Marshall et al., 2007). The Advisory Committee on Immunization Practices (ACIP) in the United States also recommends the preferential use of combination vaccines whenever feasible (National Center for Immunization and Respiratory Diseases General recommendations on immunization, 2011). Among the infectious diseases that pose serious threats to children’s health, common examples include diphtheria, poliomyelitis, pertussis, Haemophilus influenzae type b (Hib) infection, and tetanus. Traditional immunization strategies require separate administration of the Hib vaccine, inactivated poliovirus vaccine (IPV), and diphtheria-tetanus-acellular pertussis (DTaP) vaccine (Centers for Disease Control and Prevention, 2024). To achieve full immunization, infants under two years of age may need to receive up to 12 doses in total. The diphtheria-tetanus-acellular pertussis–inactivated poliovirus–Haemophilus influenzae type b combination vaccine (DTaP-IPV-Hib), widely used as a routine vaccine in pediatric immunization programs, provides simultaneous protection against five major infectious diseases. By consolidating the original 12-dose schedule into just four doses, it significantly reduces the number of injections, saves time, and improves parental and recipient compliance as well as the timeliness of vaccination (Centers for Disease Control and Prevention, 2008).

With the continuous advancement of vaccine technology and the ongoing optimization of immunization strategies, the hepatitis B vaccine (HepB) has been incorporated into the combination formulation, resulting in the development of a hexavalent vaccine (DTaP-IPV-Hib-HepB) (Oliver and Moore, 2020). This hexavalent vaccine has now been approved for routine immunization of infants and young children in numerous countries and regions. The promotion of this combination vaccine further simplifies the immunization process, reduces the complexity of vaccination schedules and parental hesitancy, and improves vaccination coverage. It aligns with the modern public health concept of “fewer injections, broader protection (Government of Canada, 2025).” Hepatitis B virus (HBV) is transmitted through blood and bodily fluids and can cause both acute and chronic hepatitis, with potential progression to liver cirrhosis and hepatocellular carcinoma. Since infection during infancy is more likely to result in chronic carrier status, the World Health Organization (WHO) recommends that all newborns receive the HepB vaccine as soon as possible after birth (World Health Organization, 2017). The introduction of the hexavalent vaccine, which retains all the protective functions of the pentavalent vaccine while additionally targeting hepatitis B prevention, offers an integrated and optimized immunization strategy (Icardi et al., 2020). However, whether the increased number of vaccine components may be linked to differences in the reporting of adverse events following immunization (AEFIs) remains a concern that warrants close attention.

Previous studies have demonstrated that both pentavalent and hexavalent vaccines exhibit good immunogenicity and overall safety (Marshall et al., 2015; Hansen et al., 2016); however, differences have been reported in both the frequency and types of adverse reactions reported. Some reports indicate that local or systemic immune responses—such as fever and injection site redness—occur slightly more frequently following administration of the hexavalent vaccine, which may be related to variations in antigen load or adjuvant composition (Marshall et al., 2015; Block et al., 2017). Nevertheless, most of these studies are based on clinical trials or controlled populations and lack systematic evaluations from large real-world datasets. Therefore, conducting large-scale, adverse event database–driven real-world analyses is of great importance to validate safety differences between the two vaccines.

The Vaccine Adverse Event Reporting System (VAERS), jointly managed by the U.S. Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC), serves as a national surveillance platform for monitoring vaccine safety and provides important insights into post-marketing safety profiles (Shimabukuro et al., 2015). In this study, we utilized the VAERS database to collect AEFIs reports associated with pentavalent and hexavalent vaccines administered to infants aged 6 weeks to 2 years between 2018 and 2024. Multiple disproportionality analysis methods were employed to detect potential safety signals and compare the types of AEFIs between the two vaccines. To account for potential confounding factors such as age and sex, multivariable logistic regression was also conducted for adjustment. The reporting patterns identified in this study may offer signal-based insights for the clinical use, safety monitoring, and immunization policy optimization of combination vaccines.

This study utilized data from the VAERS to systematically evaluate the characteristics of AEFI reports associated with the pentavalent vaccine (DTaP-IPV-Hib) and the hexavalent vaccine (DTaP-IPV-Hib-HepB) among infants aged 6 weeks to 2 years. Using four disproportionality analysis methods and multivariate logistic regression, we compared the safety signals between the two vaccines. Overall, both vaccines demonstrated favorable safety profiles. However, in our analysis, reports related to the hexavalent vaccine more frequently involved serious AEFIs and exhibited stronger and broader safety signals across multiple system organ classes, particularly within certain subgroups, highlighting the need for enhanced safety surveillance during its widespread implementation.

In terms of overall reporting characteristics, the proportion of serious AEFIs—including death, hospitalization, and life-threatening events—was significantly higher for the hexavalent vaccine compared to the pentavalent vaccine, with hospitalization and life-threatening events being particularly elevated. Previous clinical studies have reported that the incidence of serious AEFIs following hexavalent vaccination ranges from approximately 2.4% to 6.0%, which is notably higher than that observed with the pentavalent vaccine (Kosalaraksa et al., 2011; Silfverdal et al., 2016). For the latter, serious AEFIs are typically reported at a rate of 1.5 to 8 cases per 100,000 doses administered (Li et al., 2020; Pan et al., 2022). This difference in reporting patterns might be explained by the inclusion of HBV antigen in the hexavalent vaccine. The recombinant HBV surface antigen is typically adsorbed onto aluminum hydroxide adjuvant to enhance immunogenicity (Mast et al., 2005). When the HBV antigen is incorporated into the hexavalent vaccine, additional or more potent aluminum-based adjuvants are often required to ensure adequate immune response (Syed, 2019). This heightened immune stimulation may contribute to more pronounced systemic reactions, thereby increasing the proportion of reported serious AEFIs (Petrovsky and Aguilar, 2004). Although the inclusion of the hepatitis B component in the hexavalent formulation is intended to simplify the immunization schedule and improve coverage, it may also lead to more complex immune responses—particularly in young infants whose immune systems are not yet fully developed and are more susceptible to overstimulation.

At the SOC level, disproportionality analysis revealed that the hexavalent vaccine was associated with signals spanning multiple systems, including the nervous, respiratory, cardiovascular, metabolic, and musculoskeletal systems. Notably, the signal intensity for most SOCs was higher for the hexavalent vaccine compared to the pentavalent vaccine, suggesting a broader range of potential immune responses. Particular attention should be given to serious manifestations such as neurological disorders (e.g., seizure-like episodes, infantile spasms), cardiovascular events (e.g., cyanosis, arrhythmias), and respiratory depression (e.g., apnea). These findings were further supported by the distribution of specific PTs. In the nervous system domain, previous studies have shown that the hexavalent vaccine is more likely to induce fever than the pentavalent vaccine, potentially increasing the risk of febrile seizures (Kim et al., 2017; Oliver and Moore, 2020). In the respiratory system, clinical reports indicate that approximately 11%–13% of preterm infants experience apnea or bradycardia following hexavalent vaccination (Schulzke et al., 2005; Faldella et al., 2007). The European Medicines Agency has also advised that for extremely preterm infants (≤28 weeks of gestational age), the potential risk of post-vaccination apnea should be considered during the primary immunization series, recommending 48–72 hours of respiratory monitoring, especially in those with a history of respiratory immaturity (European Medicines Agency, 2020). Regarding the cardiovascular system, case reports have described sudden unexpected death in a 3-month-old girl following hexavalent vaccination. Autopsy findings revealed underdevelopment of the arcuate nucleus in the brainstem and abnormalities in the cardiac conduction system, suggesting that in infants with immature autonomic regulatory function, vaccination may trigger arrhythmias or abnormal vagal reflex responses (Ottaviani et al., 2006). Nevertheless, current evidence from clinical trials and post-marketing surveillance generally supports the overall safety of the hexavalent vaccine, with serious AEFIs remaining extremely rare (Fortunato et al., 2022). It is important to emphasize, however, that our signal detection analysis highlights the need for heightened vigilance in high-sensitivity populations, such as young infants and preterm neonates. During widespread vaccine implementation, proactive surveillance systems should be employed to facilitate comprehensive risk–benefit assessments, particularly for high-risk groups, to ensure both the safety and effectiveness of immunization strategies.

Subgroup analysis showed that the timing of vaccination corresponded to differences in reporting patterns within VAERS. Among infants aged 6 weeks to 4 months, the incidence of hexavalent vaccine–associated AEFIs was notably higher, particularly involving serious systemic reactions such as apnea, cyanosis, persistent crying, and loss of responsiveness. This phenomenon may be attributed to the fact that this developmental window represents a critical transition period in which the infant’s immune system is shifting from innate to adaptive immunity. During this stage, the immune response to multiple antigens and adjuvants may be heightened, increasing susceptibility to excessive immune activation (Sanchez-Schmitz and Levy, 2011). Previous studies have demonstrated that preterm and extremely preterm infants are at elevated risk of experiencing AEFIs such as apnea, bradycardia, and oxygen desaturation following administration of the hexavalent vaccine (Knuf et al., 2023). These findings suggest that infants in this age group may experience higher frequencies of certain reported events. Although VAERS cannot establish causality or quantify risk, enhanced post-vaccination monitoring is warranted, and careful consideration should be given to the necessity and safety of combination vaccines when designing immunization strategies for this vulnerable population.

Multivariable logistic regression analysis revealed a significant inverse association between increasing infant age and the risk of death, which may reflect the progressive maturation of the immune system during early development and improved vaccine tolerance. Moreover, reports involving female infants had lower odds of being classified as deaths. This finding is consistent with existing literature on sex-related immune differences; however, VAERS data cannot elucidate the underlying mechanisms, and factors such as differential care-seeking behavior or reporting patterns may also contribute. Although females are generally more prone to mild-to-moderate AEFIs, their risk of severe adverse outcomes appears to be lower (Klein et al., 2015). Previous studies have demonstrated sex-based differences in immune responses during infancy, with females tending toward a Th2-dominant profile characterized by antibody production and immune regulation, while males exhibit a Th1-skewed response involving cytotoxicity and inflammation (Noho-Konteh et al., 2014). Although Th1 responses may facilitate rapid pathogen clearance, they are also more likely to trigger systemic inflammatory reactions such as encephalopathy or respiratory arrest—potentially explaining the approximately 40% higher mortality risk observed in male infants (Goldman and Miller, 2012). Notably, this sex disparity is most pronounced within the first six months of life, consistent with prior findings on gender-related immunological differences. Furthermore, co-administration of vaccines was significantly associated with higher odds of reports being classified as deaths among pentavalent-related cases, whereas no such association was observed in the hexavalent group. This finding suggests that vaccine co-administration strategies may need to be tailored rather than uniformly applied across different vaccine types or populations. Instead, careful consideration of antigenic load and individual immune characteristics is warranted to avoid excessive immune burden and the potential for adverse outcomes.

Despite the use of large-scale real-world data from the VAERS database, which enhances the external validity and practical relevance of our findings, several limitations should be acknowledged. First, and most importantly, VAERS lacks denominator data (i.e., the number of doses administered), which prevents the calculation of incidence rates and means that differences in reporting frequencies between the pentavalent and hexavalent vaccines may reflect differences in vaccine uptake or reporting practices rather than true differences in safety. Second, as a passive surveillance system, VAERS is subject to underreporting, incomplete event descriptions, and reporting biases. Because VAERS is a passive surveillance system without reliable denominators, medical record adjudication, or control for stimulated reporting, these analyses describe reporting patterns and disproportionality signals only. They cannot estimate incidence or infer causality. External clinical and epidemiologic studies are needed to confirm or refute these signals. Third, the classification of AEFI severity and the assessment of causal relationships partly rely on manual standardization processes, which may introduce subjective errors or inconsistencies. Fourth, the disproportionality analysis methods employed in this study are designed to detect potential safety signals through association patterns, rather than to establish definitive causal relationships. Taken together, these limitations highlight the need for continuous improvement in vaccine safety surveillance systems and the integration of complementary data sources to support more accurate and comprehensive risk assessment.

This study, based on data from the VAERS, compared the characteristics of AEFIs associated with the pentavalent vaccine (DTaP-IPV-Hib) and the hexavalent vaccine (DTaP-IPV-Hib-HepB) in infants aged 6 weeks to 2 years. Overall, both vaccines demonstrated favorable safety profiles. However, reports for the hexavalent vaccine were more frequently for serious AEFIs and generated stronger disproportionality signals across multiple organ systems in our analysis, particularly in reports concerning younger infants. Increasing age and female sex were associated with lower odds of reports being classified as deaths, whereas vaccine co-administration was linked to higher odds of death classification within the pentavalent subset, with no clear association observed for the hexavalent subset. These findings are exploratory and hypothesis-generating, reflecting reporting patterns captured in VAERS rather than measured incidence or causality. They highlight the need for careful and focused post-vaccination monitoring, particularly among younger infants, to maintain scientific rigor and ensure the ongoing safety of immunization strategies as the hexavalent vaccine becomes more widely adopted.