Statistical and Ontological Analysis of Adverse Events Associated with Monovalent and Combination Vaccines against Hepatitis A and B Diseases

Sci Rep. 2016 Oct 3;6:34318. doi: 10.1038/srep34318.


Vaccinations often induce various adverse events (AEs), and sometimes serious AEs (SAEs). While many vaccines are used in combination, the effects of vaccine-vaccine interactions (VVIs) on vaccine AEs are rarely studied. In this study, AE profiles induced by hepatitis A vaccine (Havrix), hepatitis B vaccine (Engerix-B), and hepatitis A and B combination vaccine (Twinrix) were studied using the VAERS data. From May 2001 to January 2015, VAERS recorded 941, 3,885, and 1,624 AE case reports where patients aged at least 18 years old were vaccinated with only Havrix, Engerix-B, and Twinrix, respectively. Using these data, our statistical analysis identified 46, 69, and 82 AEs significantly associated with Havrix, Engerix-B, and Twinrix, respectively. Based on the Ontology of Adverse Events (OAE) hierarchical classification, these AEs were enriched in the AEs related to behavioral and neurological conditions, immune system, and investigation results. Twenty-nine AEs were classified as SAEs and mainly related to immune conditions. Using a logistic regression model accompanied with MCMC sampling, 13 AEs (e.g., hepatosplenomegaly) were identified to result from VVI synergistic effects. Classifications of these 13 AEs using OAE and MedDRA hierarchies confirmed the advantages of the OAE-based method over MedDRA in AE term hierarchical analysis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Female
  • Hepatitis A Vaccines / adverse effects*
  • Hepatitis B / prevention & control*
  • Hepatitis B Vaccines / adverse effects*
  • Hepatitis C / prevention & control*
  • Humans
  • Male
  • Markov Chains
  • Monte Carlo Method
  • Vaccines, Combined / administration & dosage
  • Vaccines, Combined / adverse effects*


  • Hepatitis A Vaccines
  • Hepatitis B Vaccines
  • Vaccines, Combined