Global Estimates of Vaccine-Associated Hepatic Autoimmune Disorders and Their Related Vaccines, 1968–2024: An International Analysis of the WHO Pharmacovigilance Database

While vaccines are highly effective in preventing diseases by leveraging the immune system, there is increasing concern that they may disrupt immune function and induce autoimmune diseases [1, 2]. These concerns have been particularly pronounced since the introduction of the COVID-19 vaccines [3, 4]. Previous studies have suggested an association between vaccines and autoimmune diseases, but they were constrained due to their narrow focus and period [5].

While adverse reactions to vaccines are rare, it is important to examine their contributing factors to support prevention [6]. Therefore, this study aimed, for the first time, to investigate the potential influence of various vaccines on hepatic autoimmune disorders through an international large-scale analysis.

VigiBase, managed by the World Health Organization (WHO) since 1968, is a comprehensive global database that aggregates reports of adverse drug reactions in nearly 170 countries and territories. It encompasses over 140 million cases and provides information on more than 25,000 different drugs. This study protocol was reviewed and approved by Kyung Hee University and the Uppsala Monitoring Centre, approval number (KHUH 2022-06-042). Furthermore, as this study is based on population-level data, ethical approval and informed consent were not required.

The data on vaccine-associated hepatic autoimmune disorders were collected from 1968 to 2024 and encompassed 10 categories of vaccines as follows: (1) diphtheria, tetanus toxoids, pertussis, polio, and Hemophilus influenza type b (DTaP-IPV-Hib), (2) pneumococcal, (3) influenza, (4) hepatitis B, (5) zoster, (6) papillomavirus, (7) COVID-19 mRNA, (8) Ad5-vectored COVID-19, (9) others (brucellosis, dengue virus, Ebola, encephalitis, enterovirus 7, hepatitis A, inactivated whole-virus COVID-19, leptospirosis, meningococcal, measles, mumps, rubella, mpox, plague, respiratory syncytial virus, rotavirus diarrhea, smallpox, tuberculosis, typhoid, and yellow fever vaccines). Our study utilized the Medical Dictionary for Regulatory Activities version 26.0 to collect all adverse events reported globally in vaccinated individuals based on the preferred terms listed in online supplementary Tables S1 and S2 (for all online suppl. material, see https://doi.org/10.1159/000542865). Additionally, we focused only on vaccines classified as “suspected” according to WHO causality assessment guidelines.

This study employed two commonly used pharmacovigilance indicators, the information component (IC) and the reporting odds ratio (ROR), for the analysis. For comparisons between vaccines and all reports, the unpaired Kruskal-Wallis test was used for continuous variables, while Fisher’s exact test was applied for categorical variables. Statistical significance was determined when the two-sided p value was less than 0.05. All analyses were conducted using SAS (version 9.4; SAS Inc., Cary, NC, USA).

This study utilized data from VigiBase, covering the period from 1968 to 2024, and observed a total of 8,562,584 cases of vaccine adverse events. Among these cases, 1,083 individuals were identified with vaccine-associated hepatic autoimmune disorders (Table 1). When dividing the world into six geographical regions (Fig. 1), the majority of cases were found in the European region (49.22%) and the region of the Americas (48.66%) Additionally, the non-recovery rate for this adverse effect was 27.24%, the fatality rate was 0.74%, and no deaths were reported. (online suppl. Table S3). The risk of vaccine-associated hepatic autoimmune disorders was higher in individuals aged 65 and older (45–64 years: IC, 0.64 [IC_0.25, 0.45]; ≥65 years: IC, 2.33 [IC_0.25, 2.10]). The prevalence of vaccine-associated hepatic autoimmune disorders increased slightly in 2010 due to hepatitis B and influenza vaccines and increased significantly in 2020 due to the introduction of COVID-19 mRNA vaccines (Fig. 2). The vaccine most strongly associated with these disorders was the hepatitis B vaccine (ROR, 3.52 [95% CI, 2.50–4.95]; IC, 1.76 [IC_0.25, 1.18]), followed by the COVID-19 mRNA vaccines (ROR, 2.95 [2.73–3.18]; IC, 1.40 [IC_0.25, 1.28]) and papillomavirus vaccines (ROR, 2.13 [1.45–3.13]; IC, 1.06 [IC_0.25, 0.40]). Additionally, when vaccine-associated hepatic autoimmune disorders occurred, hepatobiliary adverse events were frequently observed to occur concurrently (online suppl. Table S4).

Vaccine-associated hepatic autoimmune disorder occurred in 1,083 out of 8,562,584 all-cause vaccine adverse events (0.012%). Compared to the 82% of individuals who experienced injection site pain and the 55% who developed myalgia after receiving the COVID-19 vaccine, this is a significantly lower incidence rate [7]. However, due to the considerable burden it may impose on patients, further research is necessary [8].

The vaccine with the highest association with vaccine-associated hepatic autoimmune disorders was the hepatitis B vaccine, followed by COVID-19 mRNA vaccines and papillomavirus vaccines. Vaccines may induce these autoimmune phenomena through various mechanisms, including molecular mimicry, bystander activation, and the influences of adjuvants [3]. Additionally, vaccine-associated hepatic autoimmune disorders occurred overwhelmingly in the European region and the region of the Americas. This could be attributed to the higher prevalence of specific human leukocyte antigen genes, such as DR3 and DR4, within the populations of Europe and the Americas [9]. Additionally, the risk increased with age, and the accumulation of aged T cells, B cells, and myeloid cells could potentially act as a contributing factor [10].

While previous studies have examined the potential of vaccines like COVID-19 mRNA vaccines and papillomavirus vaccines to induce hepatic autoimmune disorders, they were limited by their short-term focus and lack of large-scale population analysis [11‒13]. In contrast, this study is the first to analyze the influences of various vaccines on hepatic autoimmune disorders over an extended period and across a large population, providing a more reliable assessment. However, this study has a limitation. The data came from a passive reporting system, which may lead to underreporting vaccine-associated hepatic autoimmune disorders, potentially underestimating the findings. Additionally, there may be biases related to national income levels. In low-income African and Asian countries, it may be challenging to detect adverse effects, leading to an underreporting bias in the recording of side effects.

In conclusion, this study suggests the potential for hepatic autoimmune disorders to occur as a result of various vaccines. Therefore, it emphasizes strengthening reporting systems to better facilitate related research. Additionally, it proposes implementing pre-vaccination screening protocols and postvaccination monitoring to address this concern.

The authors sincerely appreciate the Uppsala Monitoring Centre for granting access to and authorizing the use of the data analyzed in this study. The perspectives presented herein do not reflect the views of the Uppsala Monitoring Centre or the World Health Organization.

This study protocol was reviewed and approved by the Institutional Review Board of Kyung Hee University (approval No. KHUH 2022-06-042) and Uppsala Monitoring Centre. The use of VigiBase data for this study was authorized by the Uppsala Monitoring Centre. As the study is based on anonymized, population-level data collected through spontaneous reporting systems, ethical approval and informed consent from individual patients were not required, in accordance with the guidelines of the World Medical Association Declaration of Helsinki. The decision to exempt the study from requiring informed consent was made by the Institutional Review Board.

The authors have no conflicts of interest to declare.

This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIT; RS-2023-00248157) and the MSIT (Ministry of Science and ICT), Korea, under the ITRC (Information Technology Research Center) support program (IITP-2024-RS-2024-00438239) supervised by the IITP (Institute for Information & Communications Technology Planning & Evaluation). The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Dr. Dong Keon Yon had full access to all data in the study and took responsibility for the integrity of the data and accuracy of the data analysis. All authors have approved the final version of the manuscript before submission. Study concept and design, acquisition, analysis, and interpretation of data, drafting of the manuscript, and statistical analysis: Jinyoung Jeong, Hyesu Jo, Jaeyu Park, and Dong Keon Yon; critical revision of the manuscript for important intellectual content: Jinyoung Jeong, Hyesu Jo, Jaeyu Park, Lee Smith, Masoud Rahmati, Kwanjoo Lee, Yeonjung Ha, and Dong Keon Yon; and study supervision: Dong Keon Yon. Dong Keon Yon is the guarantor of this study. Jinyoung Jeong, Hyesu Jo, and Jaeyu Park contributed equally to this work as co-first authors. Dong Keon Yon and Masoud Rahmati contributed as the corresponding author. Dong Keon Yon is the senior author. The corresponding author attests that all listed authors meet the authorship criteria and that no others meeting the criteria have been omitted.

Jinyoung Jeong, Hyesu Jo, and Jaeyu Park contributed equally as co-first authors.Edited by: H.-U. Simon, Bern.

The data that support the findings of this study are not publicly available due to restrictions aimed at preventing their use for purposes other than research but are available from the corresponding author (D.K.Y.) upon reasonable request.