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).
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).
People |
ORCID iD |
Donald King (Primary Supervisor) |
Publications
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
BB/M017303/1 | 04/10/2015 | 03/10/2019 | |||
1646570 | Studentship | BB/M017303/1 | 04/10/2015 | 03/10/2019 |
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 | 03/2018 |
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 |