Hepatitis is a common liver disease, with viral hepatitis being one of its primary types (Cooke et al., 2024). Hepatitis A virus (HAV) and hepatitis B virus (HBV) are two important pathogens responsible for viral hepatitis. HAV is transmitted through the fecal-oral route, commonly through contaminated water, food or daily contact (Cuthbert, 2001). HBV is transmitted through blood and sexual contact (Daka et al., 2022; Fu et al., 2024). The symptoms of HAV infection manifest in the short term, including jaundice, abdominal pain and hyperbilirubinemia (Abutaleb and Kottilil, 2020). However, HBV infection causes chronic liver inflammation, which may eventually progress to cirrhosis and liver cancer (Trépo et al., 2014). In order to ensure public health, the HAV and HBV vaccines were introduced. They will prevent HAV and HBV infections by stimulating the body to produce specific antibodies. To meet broader health needs, the first Hepatitis A Inactivated and Hepatitis B (Recombinant) vaccine (Hep AB) was licensed for use in the United States in 2001 (Advisory Committee on Immunization Practices (ACIP) et al., 2006). Previous analysis showed that routine childhood vaccination would prevent 322 million cases of disease and approximately 732,000 premature deaths among children born between 1994 and 2013 (Hill et al., 2015). Viral hepatitis can also reduce its incidence through vaccination. The World Health Organization (WHO) has stated that there has been a notable decline in infection rates since the introduction of HAV and HBV vaccination (WHO position paper on hepatitis A vaccines: June 2012-recommendations, 2013; World Health Organization, 2019).

Like medications, vaccination can also induce a range of adverse events (AEs) and sometimes serious AEs (SAEs) (Li et al., 2024f; Zhang et al., 2024; Li et al., 2025e). Then, the safety of Hep AB is often a concern for vaccine recipients. The most commonly reported AEs in clinical trials were general fatigue, injection site pain, erythema and headache (Murdoch et al., 2003). Safety analysis of vaccination during pregnancy indicated that Hep AB vaccination did not show any patterns of adverse pregnancy outcomes (Celzo et al., 2020). Moreover, AEs after Hep AB vaccination were found to be similar to those reported after single-dose HAV and HBV vaccinations (Woo et al., 2006). These reports indicate a safety profile for Hep AB. The safety of Hep AB has been comprehensively evaluated prior to its market launch. Nevertheless, its long-term safety has still attracted widespread attention. Over the past decade, the safety of Hep AB vaccination has continued to be assessed. However, there has been a lack of real-world report of Hep AB vaccination in the past five years.

AE related studies in vaccine informatics have attracted significant public attention, as evidenced by recent research advancements (Li et al., 2024a, 2024b, 2025a; Pan et al., 2024; Huffman et al., 2025). These studies are essential for improving the safety monitoring of vaccines and understanding potential risks. One of the key systems used to monitor AEs is the Vaccine Adverse Event Reporting System (VAERS). This system plays a crucial role in collecting and analyzing reports of vaccine AEs, contributing to a better understanding of vaccine safety. VAERS is a passive reporting system, meaning that it relies on healthcare providers and the public to voluntarily report AEs (Li et al., 2024e, 2024c, 2024d, 2025e, 2025c, 2025b, 2025d; Moro et al., 2024; Oliveira et al., 2025). In this study, we aim to collect recent reports for Hep AB to identify AE signals. Four disproportionate analysis methods will be employed to examine AE signals. Besides the general population, we also focused on reports fstratified by gender. Overall, this study will provide valuable insights for the future evidence-based surveillance strategies of Hep AB.

The data in VAERS includes demographic details of the vaccinated individuals, types of vaccines administered and information on AE reports (Shimabukuro et al., 2015). AEs and their related signs and symptoms are coded using the Medical Dictionary for Regulatory Activities (MedDRA, version 27.0). Each report may include one or more MedDRA Preferred Terms (PTs). PTs are not necessarily medically confirmed diagnoses. This study adheres to the REporting of A Disproportionality Analysis for DrUg Safety Signal Detection Using Individual Case Safety Reports in PharmacoVigilance (READUS-PV) guidelines (Fusaroli et al., 2024).

In this study, we conducted a comprehensive analysis of AE signals following Hep AB vaccination using reports from VAERS between 2020 and 2024. Our findings indicate that the AEs observed following Hep AB vaccination are generally consistent with those listed in the package insert, including immune system disorders. In addition, we still identified unanticipated AEs, including endocrine disorders. Under gender stratification, no signals of endocrine disorders were found in males. In females, three PT-level AE signals under endocrine disorders (autoimmune thyroiditis, hypothyroidism, and Graves’ disease) were detected. Considering the continued administration of Hep AB, our findings will provide valuable insights for future evidence-based surveillance strategies of Hep AB.

Our findings suggest that females may be more susceptible to the occurrence of autoimmune thyroiditis and Graves’ disease following Hep AB vaccination. Both AEs are associated with autoimmune attacks. The signal strength is stronger in females, suggesting a potential association with gender. Gender, as a biological variable, influences the immune response to vaccination (Klein et al., 2010). Previous study has indicated that adult females exhibit stronger innate and adaptive immune responses compared to males (Klein and Flanagan, 2016). For example, plasmacytoid dendritic cells (pDCs) exposed to the TLR7 ligand in vitro resulted in higher production of interferon-α (IFN-α) in female cells compared to males (Berghöfer et al., 2006). In addition, following viral attack in adult rats, the expression of TLR pathways and pro-inflammatory genes was higher in the tissues of female rats compared to males (Hannah et al., 2008). Vaccines, as exogenous antigens, may activate a more sensitive immune response in females. Therefore, vaccination may exacerbate local or systemic inflammatory responses in females, potentially leading to autoimmune thyroiditis and Graves’ disease. Besides our research, studies on COVID-19 vaccine related AEs have also yielded similar findings (Li et al., 2024e, 2024c, 2025c, 2025b).

Epidemiological study indicates that the prevalence of autoimmune thyroid diseases in females (such as: Hashimoto’s thyroiditis and Graves’ disease) is significantly higher than in males (Vanderpump, 2011). Vaccination may act as a triggering factor, thereby enhancing susceptibility to autoimmune thyroiditis and Graves’ disease. A previous study has suggested that a positive result for anti-thyroid microsomal antibodies was observed after the second dose of the HAV vaccine (Karali et al., 2011). It is necessary to investigate whether the antigens of the hepatitis B vaccine (HBsAg) or the inactivated virus particles of the hepatitis A vaccine may have potential molecular mimicry or cross-reactivity with thyroid tissue, leading to immune system-induced attacks on thyroid cells.

In the reports we reviewed, 1,138 documented the complete onset time of vaccine-induced AEs. Almost all reports were submitted within the first month following vaccination. However, some reports indicated that AEs occurred one year after vaccination. Therefore, it is crucial to strengthen long-term surveillance of AEs following Hep AB vaccination.

In this study, although we identified unexpected AE signals, it must be acknowledged that there are certain limitations within this study. The AE signals obtained through disproportionality analysis did not include some of the common AEs in previous Hep AB clinical trial records. This suggests that future discussions on the safety of Hep AB vaccination should incorporate more real-world data and prospective evidence. Additionally, as VAERS is a passive reporting system, our results may have been influenced by the quality of AE reports, indicating that greater caution should be exercised when interpreting the findings. Finally, disproportionality analysis only detects AE signals and cannot be interpreted as indicating causality following vaccination. This requires further observational and experimental studies in the future to establish causality.

We conducted a comprehensive examination of the recent AE reports for Hep AB and identified unexpected AEs (autoimmune thyroiditis and Graves’ disease), particularly in females. These findings will provide valuable insights into future evidence-based surveillance strategies of Hep AB, ultimately facilitating more informed decisions in vaccine safety and public health policy.