BackgroundThe safety of vaccines is a critical factor in maintaining public trust in national vaccination programs. This study aimed to evaluate the safety profiles of human papillomavirus (HPV) vaccines with regard to the distribution of adverse events (AE) across gender and age, and the correlations across various AEs using the Food and Drug Administration/Centers for Disease Control and Prevention Vaccine Adverse Event Reporting System (VAERS).MethodsFor analyses, 27,348 patients aged between 9 and 25 years old with at least one AE reported in VAERS between the year of 2006 and 2017 were included. AEs were summarized into two levels: the lower level preferred term (PT) and higher level system organ classes (SOCs) based on the structure of Medical Dictionary for Regulatory Activities (MedDRA). A series of statistical analyses were applied on both levels of AEs. Zero-truncated Poisson regression and multivariate logistic regression models were first developed to assess the rate and risk of SOCs across age groups and genders. Pairwise Pearson correlation analyses and hierarchical clustering analyses were then conducted to explore the interrelationships and clustering pattern among AEs.ResultsWe identified 27,337 unique HPV vaccine reports between 2006 and 2017. Disproportional reporting of AEs was observed across age and gender in 21 SOCs (p< 0.05). The correlation analyses found most SOCs demonstrate weak positive correlations except for five pairs which were negatively correlated: skin and subcutaneous tissue disorders + injury poisoning and procedural complications; skin and subcutaneous tissue disorders + nervous system disorders; Skin and subcutaneous tissue disorders + pregnancy, puerperium and perinatal conditions; nervous system disorders + pregnancy, puerperium and perinatal conditions; pregnancy, puerperium and perinatal conditions + general disorders and administration site conditions. Nervous system disorders had the most AEs which contributed to 12,448 (46%) cases. In the further analyses of correlations between PT in nervous system disorders, the three most strongly correlated AEs were psychiatric disorders (r= 0.35), gastrointestinal disorders (r= 0.215), and musculoskeletal and connective tissue disorders (r= 0.261). We observed an inter-SOCs correlation of the PTs among AE pairs by nervous system disorders/psychiatric disorders/gastrointestinal disorders/musculoskeletal and connective tissue disorders.ConclusionsThe analyses revealed a different distribution pattern of AEs across gender and age subgroups in 21 SOC level AEs. Correlation analyses and hierarchical clustering analyses further revealed several correlated patterns across various AEs. However, findings from this study should be interpreted with caution. Further clinical studies are needed to understand the heterogeneity of AEs reporting across subgroups and the biological pathways among the statistically correlated AEs.