Structural basis of antigenic drift in FMDV O/Cathay topotype variants revealed by porcine-derived single B-cell neutralizing antibodies
4 affiliations
- 1State 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
- 2Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China
- 3Key Laboratory of Magnetism and Magnetic Functional Materials, School of Physical Science and Technology, Electron Microscopy Centre of Lanzhou University, Lanzhou University, Lanzhou, China
- 4Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, China
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.
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BibTeX
@article{li2026structural,
title = {{Structural basis of antigenic drift in FMDV O/Cathay topotype variants revealed by porcine-derived single B-cell neutralizing antibodies}},
author = {Fengjuan Li and Shanquan Wu and Shulun Huang and Lv Lv and Yimei Cao and Huifang Bao and Pu Sun and Xingwen Bai and Jiaxin Yang and Jingjing Zha and Qiongqiong Zhao and Hehe Zhang and Dong Li and Jijun He and Zaixin Liu and Pinghua Li and Zengjun Lu and Dongsheng Lei and Kun Li},
journal = {PLOS Pathogens},
year = {2026},
month = oct,
doi = {10.1371/journal.ppat.1014650},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014650},
note = {CC BY},
}
RIS
TY - JOUR
TI - Structural basis of antigenic drift in FMDV O/Cathay topotype variants revealed by porcine-derived single B-cell neutralizing antibodies
AU - Fengjuan Li
AU - Shanquan Wu
AU - Shulun Huang
AU - Lv Lv
AU - Yimei Cao
AU - Huifang Bao
AU - Pu Sun
AU - Xingwen Bai
AU - Jiaxin Yang
AU - Jingjing Zha
AU - Qiongqiong Zhao
AU - Hehe Zhang
AU - Dong Li
AU - Jijun He
AU - Zaixin Liu
AU - Pinghua Li
AU - Zengjun Lu
AU - Dongsheng Lei
AU - Kun Li
PY - 2026
DA - 2026/10/01
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014650
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014650
AB - 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.
SN - 1553-7374
SN - 1553-7366
ER -