Ontology-based Data Mining And Analysis Of Adverse Events Associated With The Three Licensed Vaccines

As one of the greatest inventions in modern medicine, vaccine has contributed greatly to the amelioration of human misery and the increase in life expectancy in the past two centuries. However, vaccinations are often accompanied with adverse events(AEs), some of which may be serious and even fatal. Understanding the vaccine AE profiles is crucial to predict potential serious AEs(SAEs) and improve vaccine safety. Therefore, vaccine pharmacovigilance is the pharmacological science relating to the collection, assessment, monitoring, and prevention of AEs with vaccine products.Based on the ontology of adverse events(OAE) method that developed by the authors in this paper, we focused on studying the AE profiles associated with three representative licensed vaccines. First, statistical and ontological analysis of AEs associated with monovalent and combination vaccines against hepatitis A and B diseases. Then, to support the vaccine-vaccine interactions(VVI) study, we designed a statistical method using logistic regression model with MCMC sampling. Second, differential AE profiles associated with BCG as a preventive tuberculosis vaccine or therapeutic bladder cancer vaccine identified by comparative ontology-based VAERS and literature meta-analysis. Third, ontology-based meta-analysis of animal and human AEs associated with licensed Brucellosis vaccines. Overall, our research results facilitate vaccine safety surveillance and benefit rational design of more secure and effective vaccines, and our research methods can also be applied to study AEs associated with other licensed vaccines.The main results of this study as following:(1) From May 2001 to January 2015 for those vaccinees aged at least 18 years old, VAERS reported 941, 3,885, and 1,624 AE cases were associated with Havrix, EngerixB, and Twinrix, respectively. After filtering with multiple statistical and bioinformatics methods, 46, 69, and 82 AEs were identified to be significantly associated with Havrix, Engerix-B, and Twinrix, respectively. Based on the OAE hierarchical classification, the statistically significant AEs were frequently found in the behavioral and neurological, immune, eye, and hepatobiliary systems. Twenty-nine AEs were classified as SAEs, and jaundice is only SAE shared by all three vaccines. Our logistic regression model identified 13 AEs being the results of VVI synergistic effects. Furthermore, classifications of these 13 AEs using OAE and Med DRA hierarchies confirmed the advantages of the OAE-based method over Med DRA in AE term hierarchical analysis.(2) From 397 VAERS BCG AE case reports, we identified 64 AEs statistically significantly associated with the BCG TB vaccine and 14 AEs with the BCG cancer vaccine. Our meta-analysis of 41 peer-reviewed journals identified 48 AEs associated with BCG as a TB vaccine and 43 AEs associated with BCG as a cancer vaccine. Among all the identified AEs, 25 AEs belong to SAEs. OAE-based analysis indicated that the AEs associated with the BCG TB vaccine were enriched in immune system, skin, and respiratory system; in contrast, the AEs associated with the BCG cancer vaccine mainly occurred in the urinary system. With these distinct AE profiles detected, this study also discovered three AEs(i.e., chills, pneumonia, and C-reactive protein increased) shared by the BCG TB vaccine and bladder cancer vaccine. Furthermore, our deep investigation of 24 BCG-associated death cases from VAERS identified the important effects of vaccinee's age, vaccine co-administration, and immunosuppressive status of vaccinee on the final BCG-associated death outcome.(3) In this study, 27 peer-reviewed publications containing animals and humans AE reports associated with these three brucellosis vaccines were manually annotated from the PubMed database. Our meta-analysis identified 20 animal AEs and 46 human AEs associated with the three vaccines. Based on the OAE hierarchical classification, these animal AEs were enriched in the immune and reproductive system that may eventually result in the occurrence of abortion or infertility. The human AEs were concentrated in the behavioral and neurological conditions, and these AEs show flu-like symptoms that are consistent with human brucellosis. Furthermore, an ANOVA statistics analysis for linear model fits was used to determine which variables in the processing of vaccination will affect the occurrence of abortion in animals. The ANOVA results indicated that three variables significantly contribute to the occurrence of abortion: animal species, vaccination dose, and vaccination route. The other two variables(i.e., animal age at vaccination and vaccine type) did not significantly contribute to the occurrence of abortion. Overall, the results of such a study led to the better understanding of brucellosis vaccine AEs, facilitating rational design of more secure and effective vaccines.