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 footand-
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.
S1 Data. VNT serological results for serotype O viruses and antisera.
S2 Data. LPBE serological results for serotype O viruses and antisera.
S3 Data. VNT serological results for serotype SAT1 viruses and antisera.
S1 Table. Foot-and-mouth disease virus details with accession numbers.
S2 Table. Pan-serotypic reference alignment of FMDV. The dataset shows the aligned VP2,
VP3 and VP1 proteins of example SAT1 and O isolates used in the study alongside representative
isolates from the other five serotypes. The four contiguous surface-exposed structural
motifs confirmed as containing antigenic sites on at least four serotypes are highlighted in red–locations are approximate due to structural differences between the serotypes. The RGD cell
surface receptor-binding motif, in the centre of the third site, is highlighted in blue.
S3 Table. Residues identified as part of epitopes on structural proteins across the six tested
serotypes of FMDV, along with corresponding positions on all serotypes.