{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T19:59:05Z","timestamp":1789588745978,"version":"build-2803163510"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T00:00:00Z","timestamp":1658448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002385","name":"Ministry of Higher Education","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002385","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004156","name":"Mahidol University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004156","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>Porcine epidemic diarrhea virus (PEDV) is the causative agent of a highly contagious enteric disease of pigs characterized by diarrhea, vomiting, and severe dehydration. PEDV infects pigs of all ages, but neonatal pigs during the first week of life are highly susceptible; the mortality rates among newborn piglets may reach 80\u2013100%. Thus, PEDV is regarded as one of the most devastating pig viruses that cause huge economic damage to pig industries worldwide. Vaccination of sows and gilts at the pre-fertilization or pre-farrowing stage is a good strategy for the protection of suckling piglets against PEDV through the acquisition of the lactating immunity. However, vaccination of the mother pigs for inducing a high level of virus-neutralizing antibodies is complicated with unstandardized immunization protocol and unreliable outcomes. Besides, the vaccine may also induce enhancing antibodies that promote virus entry and replication, so-called antibody-dependent enhancement (ADE), which aggravates the disease upon new virus exposure. Recognition of the virus epitope that induces the production of the enhancing antibodies is an existential necessity for safe and effective PEDV vaccine design. In this study, the enhancing epitope of the PEDV spike (S) protein was revealed for the first time, by using phage display technology and mouse monoclonal antibody (mAbG3) that bound to the PEDV S1 subunit of the S protein and enhanced PEDV entry into permissive Vero cells that lack Fc receptor. The phages displaying mAbG3-bound peptides derived from the phage library by panning with the mAbG3 matched with several regions in the S1-0 sub-domain of the PEDV S1 subunit, indicating that the epitope is discontinuous (conformational). The mAbG3-bound phage sequence also matched with a linear sequence of the S1-BCD sub-domains. Immunological assays verified the phage mimotope results. Although the molecular mechanism of ADE caused by the mAbG3<jats:italic>via<\/jats:italic>binding to the newly identified S1 enhancing epitope awaits investigation, the data obtained from this study are helpful and useful in designing a safe and effective PEDV protein subunit\/DNA vaccine devoid of the enhancing epitope.<\/jats:p>","DOI":"10.3389\/fmicb.2022.933249","type":"journal-article","created":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T15:28:54Z","timestamp":1658503734000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":25,"title":["Enhancing epitope of PEDV spike protein"],"prefix":"10.3389","volume":"13","author":[{"given":"Techit","family":"Thavorasak","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monrat","family":"Chulanetra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kittirat","family":"Glab-ampai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kodchakorn","family":"Mahasongkram","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nawannaporn","family":"Sae-lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karsidete","family":"Teeranitayatarn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thaweesak","family":"Songserm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rungrueang","family":"Yodsheewan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dachrit","family":"Nilubol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanpen","family":"Chaicumpa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nitat","family":"Sookrung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,22]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/j.vetimm.2015.09.006","article-title":"Age-dependent variation in innate immune responses to porcine epidemic diarrhea virus infection in suckling versus weaned pigs","volume":"168","author":"Annamalai","year":"2015","journal-title":"Vet. Immunol. Immunopathol."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"2529","DOI":"10.1038\/s41598-019-39844-5","article-title":"Identification of neutralizing monoclonal antibodies targeting novel conformational epitopes of the porcine epidemic diarrhoea virus spike protein","volume":"9","author":"Chang","year":"2019","journal-title":"Sci. Rep."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"833","DOI":"10.3390\/vaccines9080833","article-title":"Generation and characterization of a spike glycoprotein domain A-specific neutralizing single-chain variable fragment against porcine epidemic diarrhea virus","volume":"9","author":"Chang","year":"2021","journal-title":"Vaccines."},{"key":"ref4","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/S1016-8478(23)15106-5","article-title":"Identification of the epitope region capable of inducing neutralizing antibodies against the porcine epidemic diarrhea virus","volume":"14","author":"Chang","year":"2002","journal-title":"Mol. Cells"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1099\/vir.0.82537-0","article-title":"Dengue virus (DENV) antibody-dependent enhancement of infection upregulates the production of anti-inflammatory cytokines but suppresses anti-DENV free radical and pro-inflammatory cytokine production, in THP-1 cells","volume":"88","author":"Chareonsirisuthigul","year":"2007","journal-title":"J. Gen. Virol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1016\/j.virusres.2007.10.015","article-title":"The GPRLQPY motif located at the carboxy-terminal of the spike protein induces antibodies that neutralize porcine epidemic diarrhea virus","volume":"132","author":"Cruz","year":"2008","journal-title":"Virus Res."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"457","DOI":"10.3390\/vaccines9050457","article-title":"Engineered human monoclonal scFv to receptor binding domain of Ebolavirus","volume":"9","author":"Densumite","year":"2021","journal-title":"Vaccines"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"e1002111","DOI":"10.1371\/journal.ppat.1002111","article-title":"A dynamic landscape for antibody binding modulates antibody-mediated neutralization of West Nile virus","volume":"7","author":"Dowd","year":"2011","journal-title":"PLoS Pathog."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1056\/NEJMc2107799","article-title":"Infection and vaccine-induced neutralizing-antibody responses to the SARS-CoV-2 B.1.617 variants","volume":"385","author":"Edara","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"54","DOI":"10.3390\/vaccines7020054","article-title":"New rabies vaccines for use in humans","volume":"7","author":"Ertl","year":"2019","journal-title":"Vaccines"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"29201","DOI":"10.1038\/srep29201","article-title":"Antibody-dependent enhancement of dengue virus infection in primary human macrophages; balancing higher fusion against antiviral responses","volume":"6","author":"Flipse","year":"2016","journal-title":"Sci. Rep."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1128\/microbiolspec.AID-0019-2014","article-title":"Functions of antibodies","volume":"2","author":"Forthal","year":"2014","journal-title":"Microbiol. Spectr."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.vetmic.2016.11.029","article-title":"Vaccines for porcine epidemic diarrhea virus and other swine coronaviruses","volume":"206","author":"Gerdts","year":"2017","journal-title":"Vet. Microbiol."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1111\/tbed.12991","article-title":"Evolutionary and genotypic analyses of global porcine epidemic diarrhea virus strains","volume":"66","author":"Guo","year":"2019","journal-title":"Transbound. Emerg. Dis."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1179\/2046904712Z.00000000045","article-title":"Controversies in dengue pathogenesis","volume":"32","author":"Halstead","year":"2012","journal-title":"Paediatr. Int. Child Health."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1016\/0042-6822(67)90144-4","article-title":"The enhancement of virus infectivity by antibody","volume":"33","author":"Hawkes","year":"1967","journal-title":"Virology"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"2152","DOI":"10.3389\/fimmu.2020.02152","article-title":"Plant-derived trimeric co-26k-equivalent epitope induced neutralizing antibodies against porcine epidemic diarrhea virus","volume":"11","author":"Ho","year":"2020","journal-title":"Front. Immunol."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/j.micinf.2020.04.005","article-title":"The potential role of Th17 immune responses in coronavirus immunopathology and vaccine-induced immune enhancement","volume":"22","author":"Hotez","year":"2020","journal-title":"Microbes Infect."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"855","DOI":"10.1093\/infdis\/172.3.855","article-title":"Modulation of human immunodeficiency virus type 1 infection of human monocytes by IgA","volume":"172","author":"Janoff","year":"1995","journal-title":"J. Infect. Dis."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.rvsc.2018.06.009","article-title":"Immunohistochemical detection of the vomiting-inducing monoamine neurotransmitter serotonin and enterochromaffin cells in the intestines of conventional or gnotobiotic (Gn) pigs infected with porcine epidemic diarrhea virus (PEDV) and serum cytokine responses of Gn pigs to acute PEDV infection","volume":"119","author":"Jung","year":"2018","journal-title":"Res. Vet. Sci."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"198045","DOI":"10.1016\/j.viruses.2020.198045","article-title":"Porcine epidemic diarrhea virus (PEDV): An update on etiology, transmission, pathogenesis, and prevention and control","volume":"286","author":"Jung","year":"2020","journal-title":"Virus Res."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1016\/j.str.2020.12.003","article-title":"Structure and immune recognition of the porcine epidemic diarrhea virus spike protein","volume":"29","author":"Kirchdoerfer","year":"2021","journal-title":"Structure"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1007\/978-981-15-1045-8_2","article-title":"Antibody-dependent enhancement of viral infections","volume":"2019","author":"Kulkarni","year":"2020","journal-title":"Dyn. Immune Activation Viral Diseases."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1186\/s12985-015-0421-2","article-title":"Porcine epidemic diarrhea virus: An emerging and re-emerging epizootic swine virus","volume":"12","author":"Lee","year":"2015","journal-title":"Virol. J."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"e00273","DOI":"10.1128\/JVI.00273-17","article-title":"Cell attachment domains of the porcine epidemic diarrhea virus spike protein are key targets of neutralizing antibodies","volume":"91","author":"Li","year":"2017","journal-title":"J. Virol."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"104553","DOI":"10.1016\/j.micpath.2020.104553","article-title":"Porcine epidemic diarrhea virus: Molecular mechanisms of attenuation and vaccines","volume":"149","author":"Li","year":"2020","journal-title":"Microb. Pathog."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.1086\/340365","article-title":"Differing influences of virus burden and immune activation on disease severity in secondary dengue-3 virus infections","volume":"185","author":"Libraty","year":"2002","journal-title":"J. Infect. Dis."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.virusres.2016.05.023","article-title":"Evolution, antigenicity, and pathogenicity of global porcine epidemic diarrhea virus strains","volume":"226","author":"Lin","year":"2016","journal-title":"Virus Res."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"3452","DOI":"10.1016\/j.cell.2021.05.032","article-title":"An infectivity-enhancing site on the SARS-CoV-2 spike protein targeted by antibodies","volume":"184","author":"Liu","year":"2021","journal-title":"Cell"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1038\/ncb0509-510","article-title":"Virus entry by macropinocytosis","volume":"11","author":"Mercer","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"580096","DOI":"10.3389\/fcimb.2020.580096","article-title":"Intrinsic ADE: The dark side of antibody dependent enhancement during dengue infection","volume":"10","author":"Narayan","year":"2020","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/j.virol.2017.06.013","article-title":"The S2 glycoprotein subunit of porcine epidemic diarrhea virus contains immunodominant neutralizing epitopes","volume":"509","author":"Okda","year":"2017","journal-title":"Virology"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1007\/BF01317606","article-title":"A new coronavirus-like particle associated with diarrhea in swine","volume":"58","author":"Pensaert","year":"1978","journal-title":"Arch. Virol."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1097\/00002030-199708000-00002","article-title":"Two parallel routes of the complement-mediated antibody-dependent enhancement of HIV-1 infection","volume":"11","author":"Proh\u00e1szka","year":"1997","journal-title":"AIDS"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.vetmic.2008.02.022","article-title":"Identification of two novel B cell epitopes on porcine epidemic diarrhea virus spike protein","volume":"131","author":"Sun","year":"2008","journal-title":"Vet. Microbiol."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"125","DOI":"10.3390\/v14010125","article-title":"Novel neutralizing epitope of PEDV S1 protein identified by IgM monoclonal antibody","volume":"14","author":"Thavorasak","year":"2022","journal-title":"Viruses"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"653064","DOI":"10.3389\/fphar.2021.653064","article-title":"Systemic and oral immunogenicity of porcine epidemic diarrhea virus antigen fused to poly-Fc of immunoglobulin G and expressed in \u0394XT\/ft Nicotiana benthamiana plants","volume":"12","author":"Tien","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1227","DOI":"10.3201\/eid2007.140296","article-title":"Detection and genetic characterization of deltacoronavirus in pigs, Ohio, USA, 2014","volume":"20","author":"Wang","year":"2014","journal-title":"Emerg. Infect. Dis."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.coviro.2018.12.001","article-title":"Emerging and re-emerging coronaviruses in pigs","volume":"34","author":"Wang","year":"2019","journal-title":"Curr. Opin. Virol."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"1189","DOI":"10.1093\/bioinformatics\/btp033","article-title":"Jalview version 2- -a multiple sequence alignment editor and analysis workbench","volume":"25","author":"Waterhouse","year":"2009","journal-title":"Bioinformatics"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1016\/j.ijid.2020.09.015","article-title":"Antibody-dependent enhancement of coronavirus","volume":"100","author":"Wen","year":"2020","journal-title":"Int. J. Infect. Dis."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"15194","DOI":"10.1073\/pnas.1821317116","article-title":"Antibody-dependent enhancement of influenza disease promoted by increase in hemagglutinin stem flexibility and virus fusion kinetics","volume":"116","author":"Winarski","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"642","DOI":"10.3390\/vaccines8040642","article-title":"Efficacy of porcine epidemic diarrhea vaccines: A systematic review and meta-analysis","volume":"8","author":"Won","year":"2020","journal-title":"Vaccine"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/bs.ai.2021.08.003","article-title":"Antibody dependent enhancement: Unavoidable problems in vaccine development","volume":"151","author":"Xu","year":"2021","journal-title":"Adv. Immunol."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1637\/10327-081712-Reg.1","article-title":"Inhibition of toll-like receptor 2-mediated NF-kappa B activation in Vero cells with herpesvirus of turkeys","volume":"57","author":"Yang","year":"2013","journal-title":"Avian Dis."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1038\/s41541-021-00283-x","article-title":"Piglet immunization with a spike subunit vaccine enhances disease by porcine epidemic diarrhea virus","volume":"6","author":"Yu","year":"2021","journal-title":"NPJ Vaccines"}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2022.933249\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,29]],"date-time":"2024-09-29T18:09:49Z","timestamp":1727633389000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2022.933249\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,22]]},"references-count":46,"alternative-id":["10.3389\/fmicb.2022.933249"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2022.933249","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,22]]},"article-number":"933249"}}