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.

A sparse hierarchical Bayesian model for detecting relevant antigenic sites in virus evolution

“…We do this through the inclusion of variables related to different properties of the branches of the phylogenetic tree. The reconstruction of phylogenetic trees is not the subject of this article, and therefore we use trees generated from the structural proteins of SAT1, SAT2 and H1N1 viruses presented by Reeve et al (2010Reeve et al ( , 2016 and Harvey et al (2016). Where possible, for each of the branches we include variables related to the effect of the challenge and protective strains, as well as to account for unknown antigenic effects; see Section 6 of the supplementary details for more information.…”

“…Originally Reeve et al (2010) analysed the original SAT1 dataset (Sect. 4.2) and Reeve et al (2016) investigated an extended version of this dataset (Sect. 4.3).…”

“…To compare the results of the SABRE method against the mixed-effects models used in Reeve et al (2010Reeve et al ( , 2016 and Harvey et al (2016), we examine which categories (proven, plausible or implausible) the various residues selected fall into. Note that to do this we ignore any branch terms that do not directly correspond to a residue term.…”

“…More recently Reeve et al (2016) explored an extended SAT1 dataset, which includes an increased number of strains and repeated experiments, and identified a number of known antigenic residues. Reeve et al (2010) also used their methods on a small SAT2 dataset but were unable to select any significant residues in their model.…”

“…The main purpose of this paper is to develop a Sparse hierArchical Bayesian model for detecting Relevant antigenic sites in virus Evolution (SABRE) and use it to analyse the SAT1, SAT2 and H1N1 datasets from Reeve et al (2010Reeve et al ( , 2016 and Harvey et al (2016). We propose and evaluate three different versions of the SABRE method and use them to identify a number of previously unidentified residues, as well as predicting a number of sites that could be plausibly antigenic.…”