{ "abstract": "The porcinophilic O/Cathay topotype variants of foot-and-mouth disease virus (FMDV) continuously accumulated mutations over time and produced antigenic drift, leading to diminished serum neutralization and compromised vaccine efficacy. However, the structural basis underlying this divergence remains poorly defined. Herein, we observed that the newly emerging O/Cathay variants in China exhibited marked neutralization escape from porcine immune sera. Furthermore, using a panel of seven porcine-derived neutralizing monoclonal antibodies (pnAbs), we mapped two antigenic regions with crucial determinants responsible for neutralization escape in recent O/Cathay variants. The charge change at +2 residue (Q → H/R) downstream of the conserved RGD receptor-binding motif on VP1, which modulates sensitivity to multiple pnAbs (pO18-34, pO18-40 and pO18-43) and vaccine-induced sera. Cryo-electron microscopy (cryo-EM) structures of pO18-29 in complex with the ancient O/HN/CHA/93 strain and the recent variant O/18074 revealed a novel VP3-centered antigenic structure and showed that mutations at positions 73 (V → K) and 134 (K → T) on VP3 mediated neutralization escape in O/Cathay variants via disruption of hydrophobic interaction as well as the hydrogen bonds and salt bridge networks. Moreover, residues 73 and 134 synergistically regulate pnAbs (pO18-2, pO18-18, pO18-28 and pO18-29) recognition. Together, our findings elucidate structural basis of neutralizing evasion in O/Cathay FMDV and provide a molecular framework for the rational design of next-generation broad-spectrum FMDV vaccine against emerging O/Cathay variants. Author summary: Foot-and-mouth disease virus (FMDV) remains a major threat to livestock production worldwide, and the emergence of new variants can undermine the effectiveness of existing vaccines. In this study, we examined newly emerging O/Cathay FMDV variants circulating in China and found that they can evade neutralization by immune sera from vaccinated pigs. By analyzing a panel of pig-derived neutralizing monoclonal antibodies, we identified two antigenic regions that play distinct roles in mediating this neutralization escape. A charge-changing mutation near the conserved RGD receptor-binding site on the viral capsid protein VP1 reduces antibody recognition. Cryo-electron microscopy structures further revealed a previously unrecognized antigenic surface on the VP3 protein. We show that mutations at positions 73 and 134 on VP3 disrupt critical molecular interactions, including hydrophobic contacts, hydrogen bonds, and salt bridges, thereby enabling the virus to escape multiple antibodies binding. Notably, these two residues on VP3 act cooperatively to regulate antibody recognition. Together, our findings provide structural insights into how emerging FMDV variants evade immune responses and highlight specific targets for the design of broadly protective vaccines against evolving O/Cathay strains.", "abstract_shown": true, "affiliations": [ "State Key Laboratory of Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China", "Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China", "Key Laboratory of Magnetism and Magnetic Functional Materials, School of Physical Science and Technology, Electron Microscopy Centre of Lanzhou University, Lanzhou University, Lanzhou, China", "Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, China" ], "article_type": "Research Article", "arxiv": null, "author_total": 19, "authors": [ { "affs": [ 0 ], "name": "Fengjuan Li" }, { "affs": [ 1 ], "name": "Shanquan Wu" }, { "affs": [ 2 ], "name": "Shulun Huang" }, { "affs": [ 3 ], "name": "Lv Lv" }, { "name": "Yimei Cao" }, { "name": "Huifang Bao" }, { "name": "Pu Sun" }, { "name": "Xingwen Bai" }, { "name": "Jiaxin Yang" }, { "name": "Jingjing Zha" }, { "name": "Qiongqiong Zhao" }, { "name": "Hehe Zhang" }, { "name": "Dong Li" }, { "name": "Jijun He" }, { "name": "Zaixin Liu" }, { "name": "Pinghua Li" }, { "name": "Zengjun Lu" }, { "name": "Dongsheng Lei" }, { "name": "Kun Li" } ], "bibtex": "https://research.draconitic.com/paper/163swa5xyn5ky.bib", "cited_by": 0, "doi": "10.1371/journal.ppat.1014650", "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014650", "id": "163swa5xyn5ky", "issns": [ "1553-7374", "1553-7366" ], "landing_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014650", "language": "eng", "licence": "CC-BY", "licence_label": "CC BY", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "1102|Animal Disease Management and Epidemiology" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/Immune system proteins/Antibodies" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/Immune system proteins/Antigens" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/Immune system proteins/Antigens/Antigenic variation" ], [ "plos", "/Biology and life sciences/Genetics/Mutation/Substitution mutation" ], [ "plos", "/Biology and life sciences/Immunology/Immune system proteins/Antibodies" ], [ "plos", "/Biology and life sciences/Immunology/Immune system proteins/Antigens" ], [ "plos", "/Biology and life sciences/Immunology/Immune system proteins/Antigens/Antigenic variation" ], [ "plos", "/Biology and life sciences/Microbiology/Virology/Viral replication/Viral packaging" ], [ "plos", "/Biology and life sciences/Microbiology/Virology/Viral vaccines" ], [ "plos", "/Biology and life sciences/Physiology/Immune physiology/Antibodies" ], [ "plos", "/Biology and life sciences/Physiology/Immune physiology/Antigens" ], [ "plos", "/Biology and life sciences/Physiology/Immune physiology/Antigens/Antigenic variation" ], [ "plos", "/Biology and life sciences/Zoology/Animal diseases/Foot and mouth disease" ], [ "plos", "/Medicine and health sciences/Immunology/Immune system proteins/Antibodies" ], [ "plos", "/Medicine and health sciences/Immunology/Immune system proteins/Antigens" ], [ "plos", "/Medicine and health sciences/Immunology/Immune system proteins/Antigens/Antigenic variation" ], [ "plos", "/Medicine and health sciences/Medical conditions/Infectious diseases/Infectious disease control/Vaccines/Viral vaccines" ], [ "plos", "/Research and analysis methods/Microscopy/Electron microscopy/Electron cryo-microscopy" ] ], "openalex": "W7222287428", "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014650&type=printable", "pmcid": "PMC13671523", "pmid": null, "published": "2026-10-01", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/163swa5xyn5ky.ris", "sources": [ { "first_seen": "2026-10-30T12:17:23Z", "native_id": "10.1371/journal.ppat.1014650", "source": "plos", "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014650" }, { "first_seen": "2026-10-30T12:18:29Z", "native_id": "PMC:PMC13671523", "source": "europepmc", "url": "https://europepmc.org/article/PMC/PMC13671523" } ], "subjects": [ { "field": "biology", "origin": "plos:immunology", "subfield": "immunology" }, { "field": "medicine", "origin": "plos:physiology", "subfield": "physiology" } ], "title": "Structural basis of antigenic drift in FMDV O/Cathay topotype variants revealed by porcine-derived single B-cell neutralizing antibodies", "title_text": "Structural basis of antigenic drift in FMDV O/Cathay topotype variants revealed by porcine-derived single B-cell neutralizing antibodies", "type": "peer-reviewed", "updated_at": "2026-10-30T12:18:29Z", "url": "https://research.draconitic.com/paper/163swa5xyn5ky", "venue": "PLOS Pathogens", "versions": [] }