Using a 'Vaccinomics' Approach to Characterise FMDV Evolution under Vaccine Selection

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Contributing to food security and our economy, animal health is a strategic priority of the BBSRC. Our work on the development of successful animal-disease intervention strategies by producing more effective vaccines is a powerful strategy to protect our livestock, with viruses such as rinderpest already successfully eradicated. Foot-and-mouth disease virus (FMDV) has significant socio-economic effects on livestock and its eradication/outbreak control through vaccinations is of prime importance. Many RNA viruses such as FMDV exist as heterogeneous populations known as quasispecies, comprising related but non-identical genomes. Such complexity is due to their high replication rate, large population size and error-prone replication with current estimates predicting one nucleotide change occurring during each cycle of virus replication (Klein et al, 2009). Such evolutionary plasticity places significant limitations upon the strategies for the design ofefficacious vaccines that can protect against a wide range of constantly changing circulating field strains. Moreover, minor variants of FMDV, that may have an important role in transmission and quasispecies evolution with potentially serious effects on vaccine stability and efficacy (mixed-population vaccines), remain uncharacterised. Systematic investigations into the factors that effect FMDV vaccine quality in terms of characterising minor variants, quasispecies dynamics, heterogeneity and invoking a host-response are therefore critical in establishing a robust vaccination regime against FMDV outbreaks.High throughput technologies and large-scale datasets such as genomics, transcriptomics and proteomics are increasingly being exploited within vaccine development and vaccine safety research, hence the term Vaccinomics (Luciani et al, 2012). Here we employ high-throughput sequencing to address three objectives: 1. Accurately and rapidly obtain whole genomesequences (WGS) of different FMDV strains from different geographical regions to further understanding of the molecular and evolutionary mechanisms employed by FMDV quasispecies that drive immune escape and contribute to viral persistence or carrier states. (i.e. working towards an FMDV prevention program) 2. Detect and characterise minority variants and escape mutants (as low as 0.1%) to understand the heterogeneity of vaccines and the effects that this has on vaccine quality (i.e. working towards an improved/more robust vaccination program). 3. Determine the host's transcriptomic response to FMDV vaccinations, to understand the interactions between host and pathogen/vaccination that are important for providing protection (i.e. working towards a refined vaccination program). High-throughput technologies will also be used to characterise and assess aspects of vaccine quality criteria (i.e. homogeneity of seed lots and adventitious pathogens).