title: Tracking the Antigenic Evolution of Foot-and-Mouth Disease Virus.
abstract: Quantifying and predicting the antigenic characteristics of a virus is something of a holy grail for infectious disease research because of its central importance to the emergence of new strains, the severity of outbreaks, and vaccine selection. However, these characteristics are defined by a complex interplay of viral and host factors so that phylogenetic measures of viral similarity are often poorly correlated to antigenic relationships. Here, we generate antigenic phylogenies that track the phenotypic evolution of two serotypes of foot-and-mouth disease virus by combining host serology and viral sequence data to identify sites that are critical to their antigenic evolution. For serotype SAT1, we validate our antigenic phylogeny against monoclonal antibody escape mutants, which match all of the predicted antigenic sites. For serotype O, we validate it against known sites where available, and otherwise directly evaluate the impact on antigenic phenotype of substitutions in predicted sites using reverse genetics and serology. We also highlight a critical and poorly understood problem for vaccine selection by revealing qualitative differences between assays that are often used interchangeably to determine antigenic match between field viruses and vaccine strains. Our approach provides a tool to identify naturally occurring antigenic substitutions, allowing us to track the genetic diversification and associated antigenic evolution of the virus. Despite the hugely important role vaccines have played in enhancing human and animal health, vaccinology remains a conspicuously empirical science. This study advances the field by providing guidance for tuning vaccine strains via site-directed mutagenesis through this high-resolution tracking of antigenic evolution of the virus between rare major shifts in phenotype.
authors.affiliation: Boyd Orr Centre for Population and Ecosystem Health, Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.|The Pirbright Institute, Pirbright, Woking, Surrey, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Reeve
authors.affiliation: The Pirbright Institute, Pirbright, Woking, Surrey, United Kingdom.|Division of Structural Biology, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Headington, Oxford, United Kingdom.
authors.forename: Daryl W
authors.initials: DW
authors.lastname: Borley
authors.affiliation: ARC-Onderstepoort Veterinary Institute, Transboundary Animal Diseases Programme, Onderstepoort, South Africa.|Department of Microbiology and Plant Pathology, Faculty of Agricultural and Natural Sciences, University of Pretoria, Pretoria, South Africa.
authors.forename: Francois F
authors.initials: FF
authors.lastname: Maree
authors.affiliation: The Pirbright Institute, Pirbright, Woking, Surrey, United Kingdom.
authors.forename: Sasmita
authors.initials: S
authors.lastname: Upadhyaya
authors.affiliation: ARC-Onderstepoort Veterinary Institute, Transboundary Animal Diseases Programme, Onderstepoort, South Africa.
authors.forename: Azwidowi
authors.initials: A
authors.lastname: Lukhwareni
authors.affiliation: ARC-Onderstepoort Veterinary Institute, Transboundary Animal Diseases Programme, Onderstepoort, South Africa.
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Esterhuysen
authors.affiliation: Boyd Orr Centre for Population and Ecosystem Health, Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: William T
authors.initials: WT
authors.lastname: Harvey
authors.affiliation: ARC-Onderstepoort Veterinary Institute, Transboundary Animal Diseases Programme, Onderstepoort, South Africa.|Department of Production Animal Studies, Faculty of Veterinary Science, University of Pretoria, Onderstepoort, South Africa.
authors.forename: Belinda
authors.initials: B
authors.lastname: Blignaut
authors.affiliation: Division of Structural Biology, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Headington, Oxford, United Kingdom.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Fry
authors.affiliation: The Pirbright Institute, Pirbright, Woking, Surrey, United Kingdom.
authors.forename: Satya
authors.initials: S
authors.lastname: Parida
authors.affiliation: The Pirbright Institute, Pirbright, Woking, Surrey, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Paton
authors.affiliation: The Pirbright Institute, Pirbright, Woking, Surrey, United Kingdom.
authors.forename: Mana
authors.initials: M
authors.lastname: Mahapatra
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000276:immunology*; D002417:Cattle; D002460:Cell Line; D006224:Cricetinae; D004797:Enzyme-Linked Immunosorbent Assay; D018604:Epitope Mapping; D019143:Evolution, Molecular; D029544:Foot-and-Mouth Disease Virus / Q000235:genetics / Q000276:immunology*; D006041:Goats; D016296:Mutagenesis; D009500:Neutralization Tests; D010802:Phylogeny; D012703:Serotyping; D013552:Swine
chemical_list: D000956:Antigens, Viral