{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T17:14:54Z","timestamp":1772990094519,"version":"3.50.1"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T00:00:00Z","timestamp":1759449600000},"content-version":"vor","delay-in-days":33,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,8,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Venom-based therapies are hindered by traditional discovery methods that are costly and inconsistent. Immunoinformatics offers a faster route to identify immunogenic epitopes, yet its application to venom proteins remains limited. We conducted a systematic review under PRISMA-2020 guidelines to identify studies predicting venom toxin epitopes computationally and validating them experimentally. Risk of bias was evaluated using a custom 20-question checklist. Following our systematic search, 11 articles met inclusion criteria. Multitool prediction strategies consistently outperformed single-tool approaches, particularly when structural and sequence-based models were combined. Experimental validations confirmed immunogenicity through diverse assays, but reporting inconsistencies, limited negative data, and variable study designs impaired direct comparison. Toxin family and structural data availability emerged as key factors influencing prediction success. In silico epitope prediction, combined with experimental validation, holds strong promise for advancing venom research. Our systematic bias assessment underscores the critical need for standardized frameworks to evaluate dataset selection, algorithm parameters, and validation rigor in computational epitope discovery. Moreover, the field must urgently address data scarcity, standardize validation protocols, and expand venom-specific training datasets to fully realize the promise of immunoinformatics-driven discovery.<\/jats:p>","DOI":"10.1093\/bib\/bbaf519","type":"journal-article","created":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T18:44:45Z","timestamp":1759517085000},"source":"Crossref","is-referenced-by-count":2,"title":["Computational immunology in venom research: a systematic review of epitope prediction and validation approaches"],"prefix":"10.1093","volume":"26","author":[{"given":"Razana","family":"Zegrari","sequence":"first","affiliation":[{"name":"Mohammed VI University of Sciences and Health (UM6SS) , Boulevard Mohammed ta\u00efeb Naciri, Commune Hay Hassani 82 403, 20100, Casablanca,","place":["Morocco"]},{"name":"Mohammed VI Center for Research and Innovation (CM6RI), 01, Boulevard Mohamed Al Jazouli, Madinat Al Irfane, Hay Riad, 10112, Rabat, Morocco"}]},{"given":"Abderrahim Ait","family":"Ouchaoui","sequence":"additional","affiliation":[{"name":"Mohammed VI University of Sciences and Health (UM6SS) , Boulevard Mohammed ta\u00efeb Naciri, Commune Hay Hassani 82 403, 20100, Casablanca,","place":["Morocco"]},{"name":"Mohammed VI Center for Research and Innovation (CM6RI), 01, Boulevard Mohamed Al Jazouli, Madinat Al Irfane, Hay Riad, 10112, Rabat, Morocco"}]},{"given":"Zainab","family":"Gaouzi","sequence":"additional","affiliation":[{"name":"Mohammed VI University of Sciences and Health (UM6SS) , Boulevard Mohammed ta\u00efeb Naciri, Commune Hay Hassani 82 403, 20100, Casablanca,","place":["Morocco"]},{"name":"Mohammed VI Center for Research and Innovation (CM6RI), 01, Boulevard Mohamed Al Jazouli, Madinat Al Irfane, Hay Riad, 10112, Rabat, Morocco"}]},{"given":"Hanane","family":"Abbou","sequence":"additional","affiliation":[{"name":"Mohammed VI University of Sciences and Health (UM6SS) , Boulevard Mohammed ta\u00efeb Naciri, Commune Hay Hassani 82 403, 20100, Casablanca,","place":["Morocco"]},{"name":"Mohammed VI Center for Research and Innovation (CM6RI), 01, Boulevard Mohamed Al Jazouli, Madinat Al Irfane, Hay Riad, 10112, Rabat, Morocco"}]},{"given":"Rihab","family":"Festali","sequence":"additional","affiliation":[{"name":"Mohammed VI University of Sciences and Health (UM6SS) , Boulevard Mohammed ta\u00efeb Naciri, Commune Hay Hassani 82 403, 20100, Casablanca,","place":["Morocco"]},{"name":"Mohammed VI Center for Research and Innovation (CM6RI), 01, Boulevard Mohamed Al Jazouli, Madinat Al Irfane, Hay Riad, 10112, Rabat, Morocco"}]},{"given":"Rachid","family":"Eljaoudi","sequence":"additional","affiliation":[{"name":"Mohammed VI Center for Research and Innovation (CM6RI), 01, Boulevard Mohamed Al Jazouli, Madinat Al Irfane, Hay Riad, 10112, Rabat, Morocco"},{"name":"Biotechnology lab (MedBiotech), Bioinova Research Center, Medical and Pharmacy School, Mohammed V University Av. Mohamed Belarbi El Alaoui Rabat Institut, 10000, Rabat, Morocco"}]},{"given":"Saber","family":"Boutayeb","sequence":"additional","affiliation":[{"name":"Mohammed VI University of Sciences and Health (UM6SS) , Boulevard Mohammed ta\u00efeb Naciri, Commune Hay Hassani 82 403, 20100, Casablanca,","place":["Morocco"]},{"name":"Mohammed VI Center for Research and Innovation (CM6RI), 01, Boulevard Mohamed Al Jazouli, Madinat Al Irfane, Hay Riad, 10112, Rabat, Morocco"}]},{"given":"Lahcen","family":"Belyamani","sequence":"additional","affiliation":[{"name":"Mohammed VI University of Sciences and Health (UM6SS) , Boulevard Mohammed ta\u00efeb Naciri, Commune Hay Hassani 82 403, 20100, Casablanca,","place":["Morocco"]},{"name":"Mohammed VI Center for Research and Innovation (CM6RI), 01, Boulevard Mohamed Al Jazouli, Madinat Al Irfane, Hay Riad, 10112, Rabat, Morocco"},{"name":"Department of Emergency, Mohammed V Military Training Hospital, Mohammed V University of Rabat , Av. Abderrahim Bouabid,10045, Rabat,","place":["Morocco"]}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1958-9202","authenticated-orcid":false,"given":"Ilhame","family":"Bourais","sequence":"additional","affiliation":[{"name":"Mohammed VI University of Sciences and Health (UM6SS) , Boulevard Mohammed ta\u00efeb Naciri, Commune Hay Hassani 82 403, 20100, Casablanca,","place":["Morocco"]},{"name":"Mohammed VI Center for Research and Innovation (CM6RI), 01, Boulevard Mohamed Al Jazouli, Madinat Al Irfane, Hay Riad, 10112, Rabat, Morocco"},{"name":"Laboratory of Human Pathologies Biology, Faculty of Sciences, Mohammed V University, 4 Avenue Ibn Batouta, 1014, Rabat ,","place":["Morocco"]}]}],"member":"286","published-online":{"date-parts":[[2025,10,3]]},"reference":[{"key":"2025100314443916000_ref1","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxcx.2021.100079","article-title":"Clinical management of snakebite envenoming: future perspectives","volume":"11","author":"Hamza","year":"2021","journal-title":"Toxicon: X"},{"key":"2025100314443916000_ref2","doi-asserted-by":"publisher","first-page":"661457","DOI":"10.3389\/fimmu.2021.661457","article-title":"Snakebite envenoming diagnosis and diagnostics","volume":"12","author":"Knudsen","year":"2021","journal-title":"Front Immunol"},{"key":"2025100314443916000_ref3","doi-asserted-by":"publisher","first-page":"e25531","DOI":"10.1016\/j.heliyon.2024.e25531","article-title":"Revolutionizing snakebite care with novel antivenoms: breakthroughs and barriers","volume":"10","author":"Uko","year":"2024","journal-title":"Heliyon"},{"key":"2025100314443916000_ref4","doi-asserted-by":"publisher","first-page":"458","DOI":"10.3390\/toxins16110458","article-title":"Current Technologies in Snake Venom Analysis and Applications","volume":"16","author":"Roman-Ramos","year":"2024","journal-title":"Toxins (Basel)"},{"key":"2025100314443916000_ref5","doi-asserted-by":"publisher","first-page":"452","DOI":"10.3390\/toxins10110452","article-title":"Innovative immunization strategies for antivenom development","volume":"10","author":"Berm\u00fadez-M\u00e9ndez","year":"2018","journal-title":"Toxins"},{"key":"2025100314443916000_ref6","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.nbt.2017.05.005","article-title":"Guiding recombinant antivenom development by omics technologies","volume":"45","author":"Laustsen","year":"2018","journal-title":"N Biotechnol"},{"key":"2025100314443916000_ref7","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.pbiomolbio.2016.08.007","article-title":"A framework to establish credibility of computational models in biology","volume":"129","author":"Patterson","year":"2017","journal-title":"Prog Biophys Mol Biol"},{"key":"2025100314443916000_ref8","doi-asserted-by":"publisher","first-page":"1981","DOI":"10.1093\/bib\/bby063","article-title":"A brief history of bioinformatics","volume":"20","author":"Gauthier","year":"2019","journal-title":"Brief Bioinform"},{"key":"2025100314443916000_ref9","doi-asserted-by":"publisher","first-page":"e1003285","DOI":"10.1371\/journal.pcbi.1003285","article-title":"Ten simple rules for reproducible computational research","volume":"9","author":"Sandve","year":"2013","journal-title":"PLoS Comput Biol"},{"key":"2025100314443916000_ref10","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1186\/s12859-019-3269-4","article-title":"How to balance the bioinformatics data: Pseudo-negative sampling","volume":"20","author":"Zhang","year":"2019","journal-title":"BMC Bioinformatics"},{"key":"2025100314443916000_ref11","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1007\/s10989-019-09918-z","article-title":"Epitope prediction by novel Immunoinformatics approach: a state-of-the-art review","volume":"26","author":"Raoufi","year":"2020","journal-title":"Int J Pept Res Ther"},{"key":"2025100314443916000_ref12","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/978-1-0716-0389-5_6","volume-title":"Immunoinformatics","author":"Ramana","year":"2020"},{"key":"2025100314443916000_ref13","article-title":"Immunoinformatics and Epitope Prediction in the Age of Genomic Medicine","volume-title":"Genome Med","year":"2015"},{"key":"2025100314443916000_ref14","doi-asserted-by":"publisher","first-page":"1268045","DOI":"10.3389\/frma.2023.1268045","article-title":"Appraising systematic reviews: a comprehensive guide to ensuring validity and reliability","volume":"8","author":"Shaheen","year":"2023","journal-title":"Front Res Metr Anal"},{"key":"2025100314443916000_ref15","doi-asserted-by":"publisher","first-page":"247","DOI":"10.3390\/toxins14040247","article-title":"Snake Venomics: fundamentals, recent updates, and a look to the next decade","volume":"14","author":"Tan","year":"2022","journal-title":"Toxins."},{"key":"2025100314443916000_ref16","doi-asserted-by":"publisher","first-page":"11261","DOI":"10.1038\/s41598-020-66657-8","article-title":"A pan-specific antiserum produced by a novel immunization strategy shows a high spectrum of neutralization against neurotoxic snake venoms","volume":"10","author":"Ratanabanangkoon","year":"2020","journal-title":"Sci Rep"},{"key":"2025100314443916000_ref17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2017\/2680160","article-title":"Fundamentals and methods for T- and B-cell epitope prediction","volume":"2017","author":"Sanchez-Trincado","year":"2017","journal-title":"J Immunol Res"},{"key":"2025100314443916000_ref18","doi-asserted-by":"publisher","first-page":"1143437","DOI":"10.3389\/fphar.2023.1143437","article-title":"An immunoinformatic approach to assessing the immunogenic capacity of alphaneurotoxins in elapid snake venoms","volume":"14","author":"Chan","year":"2023","journal-title":"Front Pharmacol"},{"key":"2025100314443916000_ref19","doi-asserted-by":"publisher","first-page":"418","DOI":"10.3390\/toxins14060418","article-title":"Computer-aided analysis of west sub-Saharan Africa snakes venom towards the design of epitope-based poly-specific antivenoms","volume":"14","author":"Ros-Lucas","year":"2022","journal-title":"Toxins."},{"key":"2025100314443916000_ref20","doi-asserted-by":"publisher","first-page":"e184","DOI":"10.1371\/journal.pmed.0030184","article-title":"Bioinformatics and multiepitope DNA immunization to design rational snake antivenom","volume":"3","author":"Wagstaff","year":"2006","journal-title":"PLoS Med"},{"key":"2025100314443916000_ref21","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1080\/17477778.2018.1442155","article-title":"Strengthening the reporting of empirical simulation studies: introducing the STRESS guidelines","volume":"13","author":"Monks","year":"2019","journal-title":"Journal of Simulation"},{"key":"2025100314443916000_ref22","doi-asserted-by":"publisher","first-page":"4699","DOI":"10.3390\/ijms25094699","article-title":"Anti-obesity therapeutic targets studied In silico and In vivo: a systematic review","volume":"25","author":"Medeiros","year":"2024","journal-title":"Int J Mol Sci"},{"key":"2025100314443916000_ref23","doi-asserted-by":"publisher","first-page":"e11140","DOI":"10.7717\/peerj.11140","article-title":"Understanding experiments and research practices for reproducibility: an exploratory study","volume":"9","author":"Samuel","year":"2021","journal-title":"PeerJ."},{"key":"2025100314443916000_ref24","doi-asserted-by":"publisher","first-page":"14904","DOI":"10.1038\/s41598-018-33298-x","article-title":"Computational B-cell epitope identification and production of neutralizing murine antibodies against Atroxlysin-I","volume":"8","author":"Kozlova","year":"2018","journal-title":"Sci Rep"},{"key":"2025100314443916000_ref25","first-page":"781","article-title":"Bioinformatics-based design of novel antigenic B-cell linear epitopes of Deinagkistrodon acutus venom","volume":"20","author":"Cao","year":"2016","journal-title":"European Review for Medical & Pharmacological Sciences"},{"key":"2025100314443916000_ref26","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1186\/s40409-017-0128-5","article-title":"Preparation of monoclonal antibodies against gamma-type phospholipase A2 inhibitors and immunodetection of these proteins in snake blood","volume":"23","author":"Li","year":"2017","journal-title":"J Venom Anim Toxins incl Trop Dis"},{"key":"2025100314443916000_ref27","doi-asserted-by":"publisher","first-page":"775678","DOI":"10.3389\/fimmu.2021.775678","article-title":"A strategy for efficient preparation of genus-specific diagnostic antibodies for snakebites","volume":"12","author":"Long","year":"2021","journal-title":"Front Immunol"},{"key":"2025100314443916000_ref28","doi-asserted-by":"publisher","first-page":"12271","DOI":"10.1038\/s41598-023-39222-2","article-title":"Unveiling the functional epitopes of cobra venom cytotoxin by immunoinformatics and epitope-omic analyses","volume":"13","author":"Hiu","year":"2023","journal-title":"Sci Rep"},{"key":"2025100314443916000_ref29","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.toxicon.2017.10.022","article-title":"Identification of B cell recognized linear epitopes in a snake venom serine proteinase from the central American bushmaster Lachesis stenophrys","volume":"140","author":"Madrigal","year":"2017","journal-title":"Toxicon."},{"key":"2025100314443916000_ref30","doi-asserted-by":"publisher","first-page":"970","DOI":"10.1016\/j.vaccine.2009.10.135","article-title":"Design of antibody-reactive peptides from discontinuous parts of scorpion toxins","volume":"28","author":"Alvarenga","year":"2010","journal-title":"Vaccine."},{"key":"2025100314443916000_ref31","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1007\/s10517-010-0838-y","article-title":"Prediction of epitopes in closely related proteins using a new algorithm","volume":"148","author":"Davydov","year":"2009","journal-title":"Bull Exp Biol Med"},{"key":"2025100314443916000_ref32","doi-asserted-by":"publisher","first-page":"7992","DOI":"10.1016\/j.vaccine.2011.08.065","article-title":"Protection against the toxic effects of Loxosceles intermedia spider venom elicited by mimotope peptides","volume":"29","author":"De Moura","year":"2011","journal-title":"Vaccine."},{"key":"2025100314443916000_ref33","volume-title":"Induction of Neutralizing Antibodies against Mutalysin-II from Lachesis Muta Muta Snake Venom Elicited by a Conformational B-Cell Epitope Predicted by Blue Star Sting Data Base","author":"Machado-de-\u00c1vila"},{"key":"2025100314443916000_ref34","doi-asserted-by":"crossref","first-page":"278","DOI":"10.3389\/fimmu.2017.00278","article-title":"The immune epitope database and analysis resource in epitope discovery and synthetic vaccine design","volume":"8","author":"Fleri","year":"2017","journal-title":"Front Immunol"},{"key":"2025100314443916000_ref35","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbac567","article-title":"Critical review of conformational B-cell epitope prediction methods","volume":"24","author":"Cia","year":"2023","journal-title":"Brief Bioinform"},{"key":"2025100314443916000_ref36","doi-asserted-by":"publisher","first-page":"290","DOI":"10.3390\/toxins9090290","article-title":"A review and database of Snake venom proteomes","volume":"9","author":"Tasoulis","year":"2017","journal-title":"Toxins."},{"key":"2025100314443916000_ref37","doi-asserted-by":"publisher","first-page":"1166601","DOI":"10.3389\/fbioe.2023.1166601","article-title":"Venom biotechnology: casting light on nature\u2019s deadliest weapons using synthetic biology","volume":"11","author":"L\u00fcddecke","year":"2023","journal-title":"Front Bioeng Biotechnol"},{"key":"2025100314443916000_ref38","doi-asserted-by":"publisher","first-page":"6023","DOI":"10.3390\/ijms23116023","article-title":"Insights into the pharmacological effects of flavonoids: the systematic review of computer Modeling","volume":"23","author":"Taldaev","year":"2022","journal-title":"Int J Mol Sci"},{"key":"2025100314443916000_ref39","doi-asserted-by":"publisher","first-page":"97","DOI":"10.2147\/OAB.S11886","article-title":"Antigenic epitopes prediction and MHC binder of a paralytic insecticidal toxin (ITX-1) of Tegenaria agrestis (hobo spider)","volume":"2","author":"Ingale","year":"2010","journal-title":"OAB."},{"key":"2025100314443916000_ref40","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.56499\/jppres22.1469_10.6.1046","article-title":"Virtual prediction of potential immunogenic epitope of candoxin protein from Malayan krait (Bungarus candidus) venom","volume":"10","author":"Grahadi","year":"2022","journal-title":"Journal of Pharmacy & Pharmacognosy Research"},{"key":"2025100314443916000_ref41","first-page":"2161","article-title":"An Immunoinformatics approach to design synthetic peptide vaccine from Dendroaspis polylepis polylepis Dendrotoxin-K (DTX-K)","volume":"2","author":"Changbhale","year":"2012","journal-title":"J Environ Anal Toxicol"},{"key":"2025100314443916000_ref42","doi-asserted-by":"publisher","first-page":"235","DOI":"10.4103\/0971-6580.121677","article-title":"Prediction of an epitope-based computational vaccine strategy for gaining concurrent immunization against the venom proteins of Australian box jellyfish","volume":"20","author":"Alam","year":"2013","journal-title":"Toxicol Int"},{"key":"2025100314443916000_ref43","doi-asserted-by":"publisher","first-page":"e0012080","DOI":"10.1371\/journal.pntd.0012080","article-title":"Snakebite envenoming: a systematic review and meta-analysis of global morbidity and mortality","volume":"18","author":"Afroz","year":"2024","journal-title":"PLoS Negl Trop Dis"},{"key":"2025100314443916000_ref44","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.toxicon.2018.05.003","article-title":"Antivenoms: life-saving drugs for envenomings by animal bites and stings","volume":"150","author":"Guti\u00e9rrez","year":"2018","journal-title":"Toxicon."},{"key":"2025100314443916000_ref45","doi-asserted-by":"publisher","first-page":"393","DOI":"10.3390\/toxins10100393","article-title":"Antibody cross-reactivity in antivenom research","volume":"10","author":"Ledsgaard","year":"2018","journal-title":"Toxins"},{"key":"2025100314443916000_ref46","doi-asserted-by":"publisher","first-page":"163","DOI":"10.3390\/toxins9050163","article-title":"Preclinical evaluation of the efficacy of Antivenoms for snakebite envenoming: state-of-the-art and challenges ahead","volume":"9","author":"Guti\u00e9rrez","year":"2017","journal-title":"Toxins."},{"key":"2025100314443916000_ref47","doi-asserted-by":"publisher","first-page":"180","DOI":"10.3390\/toxins15030180","article-title":"Challenges and opportunities in clinical diagnostic routine of envenomation using blood plasma proteomics","volume":"15","author":"S","year":"2023","journal-title":"Toxins."},{"key":"2025100314443916000_ref48","doi-asserted-by":"publisher","first-page":"819","DOI":"10.2147\/DDDT.S65395","article-title":"Design of a new therapy to treat snake envenomation","volume":"8","author":"Shahidi","year":"2014","journal-title":"Drug Des Devel Ther"}],"container-title":["Briefings in Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bib\/article-pdf\/26\/5\/bbaf519\/64488443\/bbaf519.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bib\/article-pdf\/26\/5\/bbaf519\/64488443\/bbaf519.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T18:44:47Z","timestamp":1759517087000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bib\/article\/doi\/10.1093\/bib\/bbaf519\/8272836"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,31]]},"references-count":48,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2025,8,31]]}},"URL":"https:\/\/doi.org\/10.1093\/bib\/bbaf519","relation":{},"ISSN":["1467-5463","1477-4054"],"issn-type":[{"value":"1467-5463","type":"print"},{"value":"1477-4054","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,9]]},"published":{"date-parts":[[2025,8,31]]},"article-number":"bbaf519"}}