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

Lead Research Organisation: University of Surrey
Department Name: Microbial & Cellular Sciences

Abstract

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 of
efficacious 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 genome
sequences (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).

Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M017303/1 05/10/2015 04/10/2019
1646570 Studentship BB/M017303/1 05/10/2015 04/10/2019 David King
 
Description The genomes of many RNA viruses exist as heterologous mixtures of closely related sequences. During this project, we have taken a systematic approach to develop experimental and bioinformatics methods that can be used to investigate sequence diversity within RNA virus populations with high confidence. An 'artificial viral swarm' that was created by introducing sequence variants at known frequencies across the capsid-encoding region of FMDV was used to maximise the detection of sub-consensus variants whilst limiting the systematic errors caused by experimental processes. This optimised pipeline was subsequently applied to analyse sequence datasets collected from experimental studies that aimed to understand the evolution of FMDV in response to vaccination-induced immune pressures. These data included FMD virus sequences generated from vaccinated and/or infected cattle, as well as sequences from an in vitro model that investigated the process by which viruses "escapes" humoral immunity. These studies identified a number of capsid variants with amino acid changes located at previously identified epitope regions and other surface-exposed residues. These substitutions were found to increase in frequency over passage to become dominate within the viral population. The wide-range of sequence variants identified in these studies help understand the spectrum of antigenic epitopes that are present of the FMDV capsid surface and indicate that the process of "immune escape" is non-deterministic
Exploitation Route The tools developed in this project can be applied to other RNA viruses that cause infectious diseases of livestock and in humans
Sectors Agriculture, Food and Drink,Environment,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description NGS training course in Belgium
Amount € 500 (EUR)
Organisation University of Glasgow 
Sector Academic/University
Country United Kingdom
Start 03/2016 
End 03/2016
 
Description Travel Grant
Amount £233 (GBP)
Organisation Microbiology Society 
Sector Learned Society
Country United Kingdom
Start 04/2018 
End 04/2018
 
Description VetBioNet
Amount £30,000 (GBP)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 03/2017 
 
Description Co-supervision of project 
Organisation University of Surrey
Department School of Biosciences & Medicine
Country United Kingdom 
Sector Hospitals 
PI Contribution Co-supervision of student project
Collaborator Contribution Co-supervision of student project
Impact None yet
Start Year 2015
 
Description Link to industrial partner 
Organisation Boehringer Ingelheim
Country Germany 
Sector Private 
PI Contribution Exchanged ideas and discussed project data
Collaborator Contribution Merial partners have contributed to the design and implementation of the project and has hosted the student for a three month industrial placement.
Impact See publication output
Start Year 2015
 
Description Designed a poster for presentation at the EuFMD conference - Title: Using high throughput sequencing to characterise low-frequency diversity of foot-and-mouth disease virus during vaccine strain adaptation 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact I prepared a poster presentation for the EuFMDV conference (Presentated by Boehringer Ingelheim) in regards to the research activity between the Pirbright Institute and Boehringer Ingelheim.
Year(s) Of Engagement Activity 2018
 
Description Hands-on experiment for students at Gordon School, Woking, Surrey 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Three scientists from Pirbright (BA, DK, EH) ran a practical session at Gordon School in November 2018 to allow students to be able to trial new rapid diagnostics assays for transboundary diseases.
Year(s) Of Engagement Activity 2018
 
Description Oral Presentation at the Microbiology Society conference - Title: Application of a deep-sequencing protocol to identify immune escape variants of FMDV 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Oral Presentation of my reseach activities to other PhD students and postdoctoral scientist.
Year(s) Of Engagement Activity 2018
 
Description Post presentation at the EUROPiC conference - Title: Optimisation of a deep-sequencing protocol to identify low frequency variants of foot-and-mouth disease virus 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Poster presentation in regards to my PhD research in a workshop to other PhD students and Postdoctoral scientist.
Year(s) Of Engagement Activity 2018
 
Description Postgraduate series presentation at University of Surrey 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Provided a presentation that described the protect to researchers at the University of Surrey. Title of the talks was: Correctly detecting sub-consensus substitutions within FMDV populations"
Year(s) Of Engagement Activity 2016
 
Description Surrey County Show 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact This engagement activity was associated with a stand at the Surrey County Show in May 2018 where the work of the Institute was show-cased to the general public.
Year(s) Of Engagement Activity 2018
 
Description Teen Tech 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Participated in Teen Tech to engage with schools (year 8 and sixth formers) to encourage them to consider STEM career choices.
Year(s) Of Engagement Activity 2019
 
Description TeenTech 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Participated in TeenTech Day at Surrey Sports Park - set up and manned Pirbright Institute stand with scientific activities for Year 8 and 6th Form students
Year(s) Of Engagement Activity 2017
URL http://www.teentech.com/teentech-events/regions/surrey/
 
Description Vet Open Day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Participated in an Open Day for the School of Veterinary Medicine at The University of Surrey - representing the Pirbright Institute
Year(s) Of Engagement Activity 2017