{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T05:41:27Z","timestamp":1784180487614,"version":"3.55.0"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T00:00:00Z","timestamp":1738886400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Viral vaccines have been proven significant in protecting us against viral diseases such as COVID-19. To better understand and design viral vaccines, it is critical to systematically collect, annotate, and analyse various viral vaccines and identify enriched patterns from these viral vaccines.  <\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We systematically collected experimentally verified viral vaccines from the literature, manually annotated, and stored the information in the VIOLIN vaccine database. The annotated information included basic vaccine names, pathogens and diseases, vaccine components, vaccine formulations, and their induced host responses. Enriched patterns were identified from our systematical analysis of the viral vaccines and vaccine antigens. <\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 2,847 viral vaccines against 95 viral species (including 72 RNA viral species and 23 DNA viral species) were collected, manually annotated, and stored in the VIOLIN vaccine database. These viral vaccines used 542 vaccine antigens. A taxonomical analysis found various DNA and RNA viruses covered by the viral vaccines. These vaccines target different viral life cycle stages (e.g., viral entry, assembly, exit, and immune evasion) as identified in top ranked human, animal vaccines, and HPV vaccines. The vaccine antigen proteins also show up in different virion locations in viruses such as HRSV vaccines. Both structural and non-structural viral proteins have been used for viral vaccine development. Protective vaccine antigens tend to have a protegenicity score of &amp;gt;85% based on the Vaxign-ML calculation, which measures predicted suitability for vaccine use. While predicted adhesins still have significantly higher chances of being protective antigens, only 21.42% of protective viral vaccine antigens were predicted to be adhesins. Furthermore, our Gene Ontology (GO) enrichment analysis using a customized Fisher\u2019s exact test identified many enriched patterns such as viral entry into the host cell, DNA\/RNA\/ATP\/ion binding, and suppression of host type 1 interferon-mediated signaling pathway. The viral vaccines and their associated entities and relations are ontologically modeled and represented in the Vaccine Ontology (VO). A VIOLIN web interface was developed to support user friendly queries of viral vaccines. <\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Viral vaccines were systematically collected and annotated in the VIOLIN vaccine knowledgebase, and the analysis of these viral vaccines identified many insightful patterns.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2025.1509226","type":"journal-article","created":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T06:49:39Z","timestamp":1738910979000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Systematic collection, annotation, and pattern analysis of viral vaccines in the VIOLIN vaccine knowledgebase"],"prefix":"10.3389","volume":"15","author":[{"given":"Anthony","family":"Huffman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehul","family":"Gautam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arya","family":"Gandhi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priscilla","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Austin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kallan","family":"Roan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongqun","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,2,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1967","DOI":"10.1007\/s00705-019-04247-4","article-title":"Taxonomy of the order Mononegavirales: update 2019","volume":"164","author":"Amarasinghe","year":"2019","journal-title":"Arch. Virol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"zcad060","DOI":"10.1093\/narcan\/zcad060","article-title":"CanVaxKB: a web-based cancer vaccine knowledgebase","volume":"6","author":"Asfaw","year":"2024","journal-title":"NAR Cancer"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1599","DOI":"10.3892\/or_00001023","article-title":"HPV-16 E6 upregulation of DNMT1 through repression of tumor suppressor p53","volume":"24","author":"Au Yeung","year":"2010","journal-title":"Oncol. Rep."},{"key":"B4","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1007\/s11427-021-1964-4","article-title":"Overview of SARS-CoV-2 genome-encoded proteins","volume":"65","author":"Bai","year":"2022","journal-title":"Sci. China Life Sci."},{"key":"B5","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1186\/s12915-017-0433-z","article-title":"Q&A: What are pathogens, and what have they done to and for us","volume":"15","author":"Balloux","year":"2017","journal-title":"BMC Biol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"595768","DOI":"10.1155\/2013\/595768","article-title":"Recent advances in diagnosis, prevention, and treatment of human respiratory syncytial virus","volume":"2013","author":"Bawage","year":"2013","journal-title":"Adv. Virol."},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.639491","article-title":"VaximmutorDB: A web-based vaccine immune factor database and its application for understanding vaccine-induced immune mechanisms","volume":"12","author":"Berke","year":"2021","journal-title":"Front. Immunol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"D49","DOI":"10.1016\/j.vaccine.2008.07.039","article-title":"The biology of influenza viruses","author":"Bouvier","year":"2008","journal-title":"Vaccine"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.3390\/v15051151","article-title":"Current hepatitis C vaccine candidates based on the induction of neutralizing antibodies","volume":"15","author":"Gomez-Escobar","year":"2023","journal-title":"Viruses"},{"key":"B10","doi-asserted-by":"publisher","first-page":"e59751","DOI":"10.1371\/journal.pone.0059751","article-title":"Immunogenic and invasive properties of Brucella melitensis 16M outer membrane protein vaccine candidates identified via a reverse vaccinology approach","volume":"8","author":"Gomez","year":"2013","journal-title":"PloS One"},{"key":"B11","doi-asserted-by":"publisher","first-page":"2201","DOI":"10.1042\/CS20160786","article-title":"The human papillomavirus replication cycle, and its links to cancer progression: a comprehensive review","volume":"131","author":"Graham","year":"2017","journal-title":"Clin. Sci. (Lond)"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.870599","article-title":"Profiling COVID-19 vaccine adverse events by statistical and ontological analysis of VAERS case reports","volume":"13","author":"Guo","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"D1124","DOI":"10.1093\/nar\/gkt1133","article-title":"Updates on the web-based VIOLIN vaccine database and analysis system","volume":"42","author":"He","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/s13326-017-0169-2","article-title":"The eXtensible ontology development (XOD) principles and tool implementation to support ontology interoperability","volume":"9","author":"He","year":"2018","journal-title":"J. BioMed. Semantics"},{"key":"B15","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1007\/BF01378632","article-title":"Infectious bursal disease virus structural protein VP2 expressed by a fowlpox virus recombinant confers protection against disease in chickens","volume":"131","author":"Heine","year":"1993","journal-title":"Arch. Virol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1309\/AJCPR5VD6NSQRWBN","article-title":"HPV L1 capsid protein detection and progression of anal squamous neoplasia","volume":"135","author":"Hernandez","year":"2011","journal-title":"Am. J. Clin. Pathol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"100139","DOI":"10.1016\/j.jvacx.2021.100139","article-title":"Cov19VaxKB: A web-based integrative COVID-19 vaccine knowledge base","volume":"10","author":"Huang","year":"2021","journal-title":"Vaccine X"},{"key":"B18","doi-asserted-by":"publisher","first-page":"W5","DOI":"10.1093\/nar\/gkn201","article-title":"NCBI BLAST: a better web interface","volume":"36","author":"Johnson","year":"2008","journal-title":"Nucleic Acids Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"152","DOI":"10.3390\/pharmaceutics15010152","article-title":"Recent advances in genomics-based approaches for the development of intracellular bacterial pathogen vaccines","volume":"15","author":"Khan","year":"2022","journal-title":"Pharmaceutics"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1799","DOI":"10.1016\/j.vaccine.2013.01.056","article-title":"Adjuvant effects of interleukin-18 in DNA vaccination against infectious bursal disease virus in chickens","volume":"31","author":"Li","year":"2013","journal-title":"Vaccine"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.2196\/51007","article-title":"Adverse events of COVID-19 vaccines in the United States: temporal and spatial analysis","volume":"10","author":"Li","year":"2024","journal-title":"JMIR Public Health Surveill"},{"key":"B22","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1186\/2041-1480-3-17","article-title":"Ontology representation and analysis of vaccine formulation and administration and their effects on vaccine immune responses","volume":"3","author":"Lin","year":"2012","journal-title":"J. BioMed. Semantics"},{"key":"B23","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1186\/s12918-017-0510-5","article-title":"Ontology-based systematic representation and analysis of traditional Chinese drugs against rheumatism","volume":"11","author":"Liu","year":"2017","journal-title":"BMC Syst. Biol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1077","DOI":"10.1016\/j.cell.2020.08.021","article-title":"Emerging pandemic diseases: how we got to COVID-19","volume":"182","author":"Morens","year":"2020","journal-title":"Cell"},{"key":"B25","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1145\/2757001.2757003","article-title":"The protege project: A look back and a look forward","volume":"1","author":"Musen","year":"2015","journal-title":"AI Matters"},{"key":"B26","doi-asserted-by":"publisher","first-page":"D678","DOI":"10.1093\/nar\/gkac1003","article-title":"Introducing the Bacterial and Viral Bioinformatics Resource Center (BV-BRC): a resource combining PATRIC, IRD and ViPR","volume":"51","author":"Olson","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"W671","DOI":"10.1093\/nar\/gkab279","article-title":"Vaxign2: the second generation of the first Web-based vaccine design program using reverse vaccinology and machine learning","volume":"49","author":"Ong","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/978-1-0716-1900-1_1","article-title":"Vaccine design by reverse vaccinology and machine learning","volume":"2414","author":"Ong","year":"2022","journal-title":"Methods Mol. Biol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"3185","DOI":"10.1093\/bioinformatics\/btaa119","article-title":"Vaxign-ML: supervised machine learning reverse vaccinology model for improved prediction of bacterial protective antigens","volume":"36","author":"Ong","year":"2020","journal-title":"Bioinformatics"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01382","article-title":"Identification of new features from known bacterial protective vaccine antigens enhances rational vaccine design","volume":"8","author":"Ong","year":"2017","journal-title":"Front. Immunol."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01581","article-title":"COVID-19 coronavirus vaccine design using reverse vaccinology and machine learning","volume":"11","author":"Ong","year":"2020","journal-title":"Front. Immunol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"D347","DOI":"10.1093\/nar\/gkw918","article-title":"Ontobee: A linked ontology data server to support ontology term dereferencing, linkage, query and integration","volume":"45","author":"Ong","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"S8","DOI":"10.1186\/s13326-017-0122-4","article-title":"Mining of vaccine-associated IFN-gamma gene interaction networks using the Vaccine Ontology","author":"Ozgur","year":"2011","journal-title":"J. BioMed. Semantics"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.03224-20","article-title":"Development of DNA vaccine targeting E6 and E7 proteins of human papillomavirus 16 (HPV16) and HPV18 for immunotherapy in combination with recombinant vaccinia boost and PD-1 antibody","volume":"12","author":"Peng","year":"2021","journal-title":"mBio"},{"key":"B35","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1007\/s00705-009-0310-3","article-title":"Insights into the role and function of L2, the minor capsid protein of papillomaviruses","volume":"154","author":"Pereira","year":"2009","journal-title":"Arch. Virol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1084\/jem.20151960","article-title":"Reverse vaccinology 2.0: Human immunology instructs vaccine antigen design","volume":"213","author":"Rappuoli","year":"2016","journal-title":"J. Exp. Med."},{"key":"B37","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.virol.2013.04.013","article-title":"The papillomavirus E7 proteins","volume":"445","author":"Roman","year":"2013","journal-title":"Virology"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.3390\/v13061023","article-title":"Sendai virus-vectored vaccines that express envelope glycoproteins of respiratory viruses","volume":"13","author":"Russell","year":"2021","journal-title":"Viruses"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-800838-6.00003-5","article-title":"Virus life cycle","volume":"6","author":"Ryu","year":"2016","journal-title":"Mol. Virol. Hum. pathogenic viruses"},{"key":"B40","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/j.cell.2023.12.002","article-title":"Vaccine induction of CD4-mimicking HIV-1 broadly neutralizing antibody precursors in macaques","volume":"187","author":"Saunders","year":"2024","journal-title":"Cell"},{"key":"B41","doi-asserted-by":"publisher","first-page":"D693","DOI":"10.1093\/nar\/gky999","article-title":"Victors: a web-based knowledge base of virulence factors in human and animal pathogens","volume":"47","author":"Sayers","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1093\/database\/baaa062","article-title":"NCBI Taxonomy: a comprehensive update on curation, resources and tools","volume":"2020","author":"Schoch","year":"2020","journal-title":"Database (Oxford)"},{"key":"B43","doi-asserted-by":"publisher","first-page":"2302685","DOI":"10.1080\/21645515.2024.2302685","article-title":"A review of safety and immunogenicity of a novel measles, mumps, rubella (MMR) vaccine","volume":"20","author":"Shah","year":"2024","journal-title":"Hum. Vaccin Immunother."},{"key":"B44","doi-asserted-by":"publisher","first-page":"W216","DOI":"10.1093\/nar\/gkac194","article-title":"DAVID: a web server for functional enrichment analysis and functional annotation of gene lists, (2021 update)","volume":"50","author":"Sherman","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"B45","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1038\/sj.clpt.6100055","article-title":"GARDASIL: prophylactic human papillomavirus vaccine development\u2013from bench top to bed-side","volume":"81","author":"Shi","year":"2007","journal-title":"Clin. Pharmacol. Ther."},{"key":"B46","doi-asserted-by":"publisher","first-page":"30494","DOI":"10.2807\/1560-7917.ES.2017.22.13.30494","article-title":"GISAID: Global initiative on sharing all influenza data - from vision to reality","volume":"22","author":"Shu","year":"2017","journal-title":"Euro Surveill"},{"key":"B47","doi-asserted-by":"publisher","first-page":"125","DOI":"10.3390\/pathogens12101259","article-title":"Respiratory syncytial virus vaccines: A review of the candidates and the approved vaccines","volume":"12","author":"Topalidou","year":"2023","journal-title":"Pathogens"},{"key":"B48","doi-asserted-by":"publisher","first-page":"D523","DOI":"10.1093\/nar\/gkac1052","article-title":"UniProt: the universal protein knowledgebase in 2023","volume":"51","author":"Uniprot","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"B49","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1186\/1756-0500-3-175","article-title":"OntoFox: web-based support for ontology reuse","volume":"3","author":"Xiang","year":"2010","journal-title":"BMC Res. Notes"},{"key":"B50","doi-asserted-by":"publisher","first-page":"D923","DOI":"10.1093\/nar\/gkm1039","article-title":"VIOLIN: vaccine investigation and online information network","volume":"36","author":"Xiang","year":"2008","journal-title":"Nucleic Acids Res."},{"key":"B51","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/2041-1480-6-4","article-title":"Ontorat: automatic generation of new ontology terms, annotations, and axioms based on ontology design patterns","volume":"6","author":"Xiang","year":"2015","journal-title":"J. BioMed. Semantics"},{"key":"B52","doi-asserted-by":"publisher","first-page":"D1073","DOI":"10.1093\/nar\/gkq944","article-title":"Protegen: a web-based protective antigen database and analysis system","volume":"39","author":"Yang","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"B53","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/s13326-024-00312-3","article-title":"Empowering standardization of cancer vaccines through ontology: enhanced modeling and data analysis","volume":"15","author":"Zheng","year":"2024","journal-title":"J. BioMed. Semantics"}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2025.1509226\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T06:49:44Z","timestamp":1738910984000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2025.1509226\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,7]]},"references-count":53,"alternative-id":["10.3389\/fcimb.2025.1509226"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2025.1509226","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,7]]},"article-number":"1509226"}}