Table 4_Comparative safety evaluation of pentavalent (DTaP-IPV-Hib) and hexavalent (DTaP-IPV-Hib-HepB) vaccines in infants: a real-world analysis based on VAERS.docx

BackgroundCombination 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.
ObjectiveThis 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.
MethodsAEFIs 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.
ResultsA 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.
ConclusionsWhile 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.

背景：联合疫苗可简化免疫接种程序、提升接种依从性，是全球儿童免疫规划的重点发展方向。无细胞百白破-灭活脊髓灰质炎-b型流感嗜血杆菌联合（DTaP-IPV-Hib）五价疫苗已得到广泛应用，在此基础上加入乙型肝炎疫苗（HepB）后，研发出了无细胞百白破-灭活脊髓灰质炎-b型流感嗜血杆菌-乙型肝炎联合（DTaP-IPV-Hib-HepB）六价疫苗。然而，六价疫苗配方中新增抗原是否与免疫接种后不良事件（Adverse Events Following Immunization, AEFIs）的报告差异存在关联，仍是学界持续争论的议题。
研究目的：本研究旨在依托美国疫苗不良事件报告系统（Vaccine Adverse Event Reporting System, VAERS）的真实世界数据，对比6周至2岁婴儿接种五价疫苗与六价疫苗后的安全性特征及AEFIs报告差异。同时，本研究还计划识别潜在安全性信号，并评估报告中死亡分类的相关影响因素。
研究方法：本研究分析了2018年至2024年间上报至VAERS的AEFIs报告。研究采用4种不成比例分析方法，包括报告比值比（Reporting Odds Ratio, ROR）、比例报告比（Proportional Reporting Ratio, PRR）、贝叶斯置信传播神经网络（Bayesian Confidence Propagation Neural Network, BCPNN）以及多项目伽马泊松收缩器（Multi-Item Gamma Poisson Shrinker, MGPS），用于识别潜在安全性信号。此外，本研究采用多变量logistic回归模型，探究与死亡分类报告相关的影响因素。
研究结果：本研究共纳入4980份AEFI报告，其中五价疫苗组3259份，六价疫苗组1720份。相较于五价疫苗接种后的报告，六价疫苗接种后的报告中严重AEFIs占比更高，尤以住院与危及生命事件为甚，该差异在6周至4月龄的婴儿中尤为显著；该年龄段婴儿中呼吸暂停与发绀的报告频率也更高。不成比例分析结果显示，六价疫苗报告在多个系统中呈现出更强的不成比例安全性信号，包括神经系统疾病（ROR=1.95；IC025=0.70）、血管疾病（ROR=2.89；IC025=1.17）、心脏疾病（ROR=1.92；IC025=0.45）以及呼吸系统疾病（ROR=1.33；IC025=0.19）。多变量模型结果显示，年龄增长与女性性别均与死亡分类报告的更低比值比相关。在五价疫苗亚组中，与其他疫苗联合接种与死亡分类报告的更高比值比相关，而在六价疫苗亚组中未观察到明确关联。
研究结论：尽管两种疫苗的报告总体上与已知安全性特征相符，但六价疫苗的报告在低龄婴儿中呈现出更强的不成比例安全性信号。本研究结果可为后续研究提供假说方向，强调了针对性接种后监测的重要性，但并未确立因果关联。