Identifying epitopes that induce antibody mediated protection against foot-and-mouth disease using reverse genetics

Lead Research Organisation: The Pirbright Institute
Department Name: UNLISTED

Abstract

Foot-and-mouth disease virus (FMDV) is the causative agent of a highly contagious and economically devastating disease of cloven hoofed domestic and wild animals. FMD is the single most important constraint to international trade in live animals and animal products. The disease is generally controlled by restriction of animal movement and slaughter of infected and in-contact animals which is very costly and unpopular with the public. The recent outbreaks in the United Kingdom in 2001, have significantly increased public awareness of this disease and now there is heightened interest in a strategy that encompasses a 'vaccinate to-live-policy' to complement stamping out as a means of controlling FMD outbreaks. Vaccinated animals produce antibodies which are believed to be important in providing protection against FMD. However, it is not well understood how such antibodies provide protection nor which parts of the virus are most important to be recognised for protection to be optimal. There are many variants of the FMD virus and multiple vaccine strains are needed to protect against all of these. Current methods to select the most appropriate vaccine are not well standardised or reliable because of dependence on antisera raised in animals that do not react to vaccination in a consistent manner. This project will use genetic engineering to construct a series of closely related FMD viruses in which individual features on the surface of the virus shell will have been slightly altered so as to affect antibody recognition. By looking at how well each of these viruses is recognised by antibodies from immune animals and by seeing how well each virus is able to induce a FMD protective immune response, we shall build up a picture of the contribution of each feature to antibody mediated protection. A better understanding of which viral structures are needed to induce a protective immune response will enable us to make accurate and much more rapid predictions of which vaccines have the necessary configurations to offer protection against a new strain of FMDV. This will be of enormous benefit when faced with the decision of whether and where to apply emergency vaccination in the face of a new FMD incursion, since the effectiveness of any vaccination programme is heavily dependent on the speed of its implementation. This knowledge will also be of fundamental value in efforts to develop broader spectrum FMD vaccines that would dramatically improve the prospects for global FMD control and eradication.

Technical Summary

FMDV causes a highly contagious and economically devastating disease of domestic animals and is generally controlled by vaccination in endemic countries and restriction of animal movement and slaughter of infected and in-contact animals in FMD-free countries. The recent 2001 outbreaks in the United Kingdom have significantly increased public awareness of this disease and now there is heightened interest in a 'vaccinate to-live-policy'. Current FMD vaccines are serotype specific and may fail to protect fully against subtypes. Vaccines therefore have to be selected, currently based on serological match between vaccine strain and field isolate. The mechanism for FMD vaccine induced protection is not clear with respect to both the viral determinants of protection and the role of different immune responses. Antibody mediated protection is believed to be an important component as there is a strong correlation between antibody titre and protection. Various neutralising epitopes have been identified on the surface of the FMD virus using murine MAb escape mutants. In addition there is evidence for the existence of other non-neutralising epitopes that are believed to play a significant role. The relative importance of different epitopes has not been ascertained. This project will help to define viral determinants of antibody mediated protection which will help in the development of sequence-based vaccine selection methods and novel broadly cross-reactive vaccines. Using reverse genetics approach a recombinant virus will be generated that is identical to its parent except that the major antigenic sites will be mutated until no serological cross-reaction between the mutant and its parent. Once it has been shown that the mutant virus does not elicit antibodies able to protect against a parental virus infection, the contribution of the different epitopes to serological recognition and in vivo protection will be established by reconstituting each epitope one at a time.

Publications

10 25 50

 
Description The research carried out in this project identified new immunogenic epitopes on the surface of the foot and mouth disease virus that contributes to vaccine induced protection. It extends our knowledge of the surface features of the FMDV capsid known to elicit neutralizing antibodies, and will improve our strategies for vaccine strain selection and rational vaccine design.
Exploitation Route The findings could be used to improve the existing vaccine strain selection methods for FMD virus.
Sectors Agriculture, Food and Drink,Education,Pharmaceuticals and Medical Biotechnology

 
Description An effective vaccination programme for the eradication of foot-and-mouth disease from India
Amount £673,500 (GBP)
Funding ID BB/L004828/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 11/2014 
End 02/2018
 
Title use of reverse genetics to study changes in capsid amino acids in foot-and-mouth disease virus 
Description Usually epitopes are identified by monoclonal antibody (mAb) escape mutant studies which is labor intensive and time consuming and also requires access to mAbs. In this study we have showed that epitopes can be predicted by correlating genetic information and serological information, and validated by making mutations in a cDNA clone using reverse genetics. This is a quicker way to identify epitopes recognized by the target species rather than mouse which may not be the target species for each pathogen we study. 
Type Of Material Improvements to research infrastructure 
Year Produced 2014 
Provided To Others? Yes  
Impact This research showed that epitopes in FMDV or other Picornaviruses can be predicted by correlating genotype to antigenic phenotype, so as by other methods. However whether the predicted epitopes are real or not can be ascertained by testing them in an infectious clone. This was done in serotype O FMDV under this grant. Following this the same was carried out in serotype A and SAT2 by other researchers which broadens our knowledge on protective epitopes on the surface of the capsid of viral pathogens.. 
 
Title FMD virus capsid sequence 
Description This project has generated capsid sequence data for several FMD virus isolates that has been submitted to public database (NCBI) and are being used by other scientists for their work. 
Type Of Material Database/Collection of data 
Year Produced 2014 
Provided To Others? Yes  
Impact This project has generated capsid sequence data for a number of FMD viruses that has been submitted to public database (NCBI) and are being used by other scientists for their work. 
URL https://www.ncbi.nlm.nih.gov/nuccore/KJ415246
 
Description Collaboration to develope vaccine matching model for FMDV 
Organisation Glasgow Life
Country United Kingdom 
Sector Private 
PI Contribution We have generated lot of serology and capsid sequence data for serotype O and A FMD viruses in our project which our collaborator at Glasgow University has used to develop models for rapid vaccine matching for serotype O FMD virus. Once validated this model will make everybody's life a lot easier where FMDV vaccines can be recommended without recourse to actual serological tests.
Collaborator Contribution Our collaborator in Glasgow University has developed a non-linear model using genetic and antigenic data thereby making FMDV vaccine matching a lot easier and less time consuming.
Impact Resulted in several publications in peer reviewed journals. 1. Reeve R, Borley D, Maree F, Upadhyaya S, Lukhwareni A, Esterhuysen J, Satya Parida, Mahapatra M. (2016). Tracking the Antigenic Evolution of Foot-and-Mouth Disease Virus. PLoS One, 11 (7), pp. e0159360. 2. Mahapatra M, Statham B, Li Y, Hammond J, Paton D, Parida S.2016. Emergence of antigenic variants within serotype A FMDV in the Middle East with antigenically critical amino acid substitutions. Vaccine. 2016 Mar 23. pii: S0264-410X(16)00238-3. doi: 10.1016/j.vaccine.2016.02.057. 3. Mahapatra M, Yuvaraj S, Madhanmohan M, Subramaniam S, Pattnaik B, Paton DJ, Srinivasan VA, Parida S (2014). Antigenic and genetic comparison of foot-and-mouth disease virus serotype O Indian vaccine strain, O/IND/R2/75 against currently circulating viruses. Vaccine. 2015 Jan 29; 33(5):693-700. 4. Mahapatra M, Parida S. Foot and mouth disease vaccine strain selection: current approaches and future perspectives. Expert Rev Vaccines. 2018 Jul;17(7):577-591. doi: 10.1080/14760584.2018.1492378.
Start Year 2010
 
Description Pirbright institute open day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact In the Pirbright Institute Open day in July 2014, the institute hosted general public, undergraduate and post-graduate students, general veterinary practioners and as well as scientists from the UK where there was opportunity to talk about the outcome of the research awarded in this grant. it was very positively received by the participants.
Year(s) Of Engagement Activity 2014