Improving the quality of FMD vaccines by understanding the correlation of vaccine-induced protection with humoral and cellular immune responses
Lead Research Organisation:
The Pirbright Institute
Department Name: Livestock Infectious Diseases
Abstract
Foot-and-mouth disease (FMD) is a highly contagious disease of cloven-hoofed domestic and wild animals with a global distribution. It remains widespread in developing countries including those of sub-Saharan Africa and South Asia, where it seriously affects livestock productivity through weight loss, decrease in milk yield and loss of draught power. This damage is greatly exacerbated by the cost of control measures and the restrictions imposed on the trade of animals and their products within and from FMD-infected areas reducing output and investment in agriculture. FMD can be controlled by restricting animal movements, by slaughtering affected animals and by vaccination; the latter being used continuously in countries where the disease is common and as an emergency measure if disease is newly introduced. FMD virus (FMDV) is in the genus Aphthovirus and the family Picornaviridae. It exists as 7 immunologically distinct types (serotypes) with little or no cross-protection between them. New variant viruses emerge periodically and may be poorly controlled by immunity to existing subtypes of the same serotype. Consequently, vaccine strain requirements differ according to the types and subtypes of virus prevailing in or threatening different regions and vaccines have to be selected with care. To inform this selection process requires collection of circulating viruses and determination of their match to existing vaccine strains, followed where necessary by development of new vaccine strains. Vaccination using killed virus grown in large cell cultures is critical to FMD control in developing countries where the weakness of veterinary services and lack of animal movement controls preclude reliance on other measures. However, current vaccines provide only short-lived protection (~6 months) that is serotype-specific and sometimes strain-specific. Each batch of the vaccine also needs to be tested in animals with live FMDV challenge to ensure quality and potency. This requires costly high containment facilities that may be unavailable or pose a risk of virus escape. These challenges to vaccine-mediated FMD control programmes have led to the virtual abandonment of attempts to establish FMD surveillance and control programmes in many parts of the developing world and to a lack of vaccine strains tailored for some regions. This project seeks to overcome the above-mentioned constraints to developing effective vaccine-based control strategies in developing countries. This will be achieved by three complementary initiatives. Firstly, vaccine strains will be selected that are appropriate for Eastern Africa, and associated to this work, the methodology for selecting vaccine strains will be simplified, bringing benefits to other regions as well. Secondly, novel adjuvants that have been identified for use in human vaccine formulations and that could enhance the potency and duration of vaccine-induced protection will be evaluated for FMD control. Thirdly, new methodology will be developed and validated to enable batch testing of FMD vaccines based on analysis of the immune responses of vaccinated animals, without a requirement to challenge these animals with virulent live virus. The combination of the use of novel adjuvants to increase the potency and duration of protection, better vaccine matching to induce more targeted coverage of circulating strains, and the increased use of in vitro assays to reduce the costs of vaccine testing could provide a significant breakthrough in the cost-effectiveness of vaccine use and hence FMD control in sub-Saharan Africa and South Asia.
Technical Summary
Foot-and-mouth disease virus (FMDV) causes a contagious and devastating disease of domestic animals (FMD) and vaccination is of paramount importance for its control in developing countries. However, vaccine-mediated protection is short-lived, making vaccination policies hard to afford. Current FMD vaccines are serotype specific and may fail to protect fully against subtypes. Consequently, vaccine strains have to be selected, based on cumbersome and difficult to standardise serological matching methods. Batch testing of vaccine efficacy is essential to guarantee the quality of vaccines but current potency tests require costly and risky challenges of vaccinated animals with virulent live virus. In order to improve vaccine selection, the project will target East Africa, where there is a diversity of circulating viruses and lack of tailored vaccine strains. This deficit will be overcome by serological characterisation of field isolates and vaccine strains. The genes encoding the virion proteins of these viruses will be sequenced to determine genetic determinants of their antigenic phenotypes and to develop a sequence-based vaccine selection method to replace the current serological approaches. This will have world-wide application to vaccine strain selection and to design of more broadly cross-reactive vaccines. To avoid reliance on live virus animal challenges in vaccine testing, the project will develop a mathematical model for predicting protection from the immune responses of vaccinated animals, combining serological data with novel measures of cell-mediated immunity. This technology will be transferred to African and Asian partners. It is hypothesised that the efficacy and duration of immunity of FMD vaccines can be improved by strengthening both the Th1 and Th2 responses and that this should be possible by introduction of novel TLR agonists that will be analysed for this use, thereby making FMD vaccines more affordable in developing countries.
Planned Impact
Foot-and-mouth disease is an important cause of loss of productivity and due to its rapid spread is considered to be the single most important constraint to international trade in animals and animal products. It is very difficult for small-scale livestock producers to take unilateral actions to protect against the effects of FMD, since the virus spreads readily from their neighbours and prevents them from marketing their products abroad. This in turn leads to a reduction in inward investment to improve productivity and output. Furthermore, since the seriousness of the losses incurred during FMD outbreaks is directly related to the productivity of the animals, it makes it difficult for livestock keepers to move beyond subsistence agriculture. Better FMD vaccines are the key to improved FMD control in developing countries. They can be used by individual farmers to protect their animals from direct losses, and form the basis for national/regional control schemes to reduce and eventually curtail virus circulation. There is a growing body of opinion that access to international markets for certain animal products such as deboned beef need not be dependent on achieving national control of FMD. Instead, FMD-free compartments could be established from which these commodities could be safely exported, providing that there are adequate quarantine facilities and crucially that appropriate and efficacious vaccines are available. This project has specifically targeted a number of practical measures that would make a significant impact on the availability of appropriate vaccines and thereby encourage the development of new vaccine-based FMD control programmes to help developing countries. In parts of East Africa, there are regions where profitability of livestock production could be significantly improved if FMD control were better. Therefore, the project has targeted the selection of new vaccine strains that would be tailored to the needs of this region. These local benefits could be realised within or shortly after the life of the project, as there are regional (as well as distant) vaccine manufacturers in Botswana and Kenya that could rapidly introduce these new vaccine strains. The project also addresses the wider need to develop simplified vaccine selection techniques that could be applied, also in the short term, to improve availability of suitable vaccine strains. The project also looks to introduce vaccines with greater potency and duration of protection, developments that would significantly improve the cost-benefit of vaccine-based control schemes in developing countries. Since the approach is based on novel adjuvants and retains the existing procedure for manufacturing vaccine antigens, it is envisaged that these developments could lead to new registered products in a relatively short timescale - perhaps 3-5 years after completion of the project. Finally, long experience of vaccine-based FMD control in South America made clear that without proper batch testing, it was impossible to guarantee the quality of vaccines on the market and without this, confidence in vaccine-based control was soon under-mined. The project therefore provides a novel approach to improving vaccine efficacy testing that could also be introduced shortly after the end of the project's life. Although targeted at problems for the developing world for FMD control, some of the outputs of this project would also be expected to contribute to FMD control in the developed world, where experience with the massive culling of animals required to control FMD in UK in 2001 has led to a desire to place greater emphasis on vaccination as a means of FMD control.
Organisations
- The Pirbright Institute (Lead Research Organisation, Project Partner)
- Scottish Government (Co-funder)
- Department for International Development (Co-funder)
- UNIVERSITY OF GLASGOW (Collaboration)
- Indian Immunologicals Ltd (Collaboration)
- Onderstepoort Veterinary Institute (Collaboration)
- University of Oxford (Project Partner)
- Ministry of Agriculture, Animal Industry and Fisheries (Project Partner)
Publications
Asfor AS
(2014)
Novel antibody binding determinants on the capsid surface of serotype O foot-and-mouth disease virus.
in The Journal of general virology
Bari FD
(2015)
Prediction and characterization of novel epitopes of serotype A foot-and-mouth disease viruses circulating in East Africa using site-directed mutagenesis.
in The Journal of general virology
Casey-Bryars M
(2018)
Waves of endemic foot-and-mouth disease in eastern Africa suggest feasibility of proactive vaccination approaches.
in Nature ecology & evolution
Chu J
(2012)
Adenovirus Expressing Human Interferon Inhibits Replication of Foot and Mouth Disease Virus and Reduces Fatal Rate in Mice
in Journal of Bacteriology and Virology
Harvey WT
(2016)
Identification of Low- and High-Impact Hemagglutinin Amino Acid Substitutions That Drive Antigenic Drift of Influenza A(H1N1) Viruses.
in PLoS pathogens
Lembo T
(2013)
Peste des petits ruminants infection among cattle and wildlife in northern Tanzania.
in Emerging infectious diseases
Lloyd-Jones K
(2017)
Genetic and antigenic characterization of serotype O FMD viruses from East Africa for the selection of suitable vaccine strain.
in Vaccine
Ludi AB
(2014)
Antigenic variation of foot-and-mouth disease virus serotype A.
in The Journal of general virology
Maake L
(2020)
Genetic Basis of Antigenic Variation of SAT3 Foot-And-Mouth Disease Viruses in Southern Africa
in Frontiers in Veterinary Science
Description | 1. Current A serotype FMD vaccines used in Eastern Africa do not provide protection against circulating viruses. 2. We have selected new vaccine strains that provide broad cross protection for almost all recently circulating viruses in East Africa. 3. We have demonstrated a potent TLR III adjuvant that helps to stimulate FMD vaccine to provide both humoral and cell-mediated responses (CD4+ and CD8+) responses and increased the duration of immunity up to minimum for six months. 4. The project had demonstrated a vaccine induced correlation protection with neutralising antibody and Interferon-Y responses. 5. Established serotype O FMD vaccine provide protection against circulating viruses in East Africa, South East Asia and Middle East.. |
Exploitation Route | An Industry is taking forward the new vaccine strains and adjuvant selected in the projects to formulate a new vaccine for use in East Africa. |
Sectors | Agriculture Food and Drink Communities and Social Services/Policy Creative Economy Education Healthcare Government Democracy and Justice Manufacturing including Industrial Biotechology |
Description | All the National Governments in East Africa and vaccine producers are now aware that Serotype A FMD vaccine strains currently used are not protective. Therefore FMD vaccine industries are engaged to adapt new vaccine that provide broad cross protection against circulating viruses. We had extended the wok to FMD virus serotype O vaccine strain selection for East Africa. The published results showed that the existing vaccines for O serotype provide protection to circulating viruses. Serotype O vaccines of Middle East origin were found to be the best protective vaccines. We have demonstrated that adding TLR III receptor to the existing vaccine formulation one can increase the duration of immunity. Vaccine industries have discussed this with the PI how to take forward on this. |
First Year Of Impact | 2019 |
Sector | Agriculture, Food and Drink,Communities and Social Services/Policy,Education,Healthcare,Government, Democracy and Justice,Manufacturing, including Industrial Biotechology |
Impact Types | Societal Economic |
Description | Improving the duration of immunity for FMD vaccine |
Amount | £201,000 (GBP) |
Funding ID | BB/N012682/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 04/2016 |
End | 05/2017 |
Title | Appropriate FMD vaccine strains for East Africa and South East Asia and new adjuvants for FMD vaccines that provide longer duration immunity |
Description | We have identifies appropriate Vaccine strains for Serotyoe O and A for East Africa and for South east Asia which are published now. Additionally we have identified potent and safe adjuvants which has been tested in cattle and provides longer duration immunity. |
Type Of Material | Improvements to research infrastructure |
Year Produced | 2014 |
Provided To Others? | Yes |
Impact | Governments of East Africa and Regional OIE centre at South East Asia and vaccine producers are aware about the strains and adjuvants. |
Title | Human former seasonal Influenza A(H1N1) haemagglutination inhibition data 1977-2009 from the WHO Collaborating Centre for Reference and Research on Influenza, London, UK |
Description | In total, 48,707 HI titers measured between 29,600 unique combinations of virus and antiserum are included. Viruses were originally isolated from clinical specimens either by WHO National Influenza Centres or by the WHO Collaborating Centre for Reference and Research on Influenza, London, UK, now the Crick Worldwide Influenza Centre, The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London, NW7 1AA, UK. The HI dataset includes 506 former seasonal A(H1N1) viruses for which HA gene sequence data was matched, for which a table of GISAID Isolate IDs is included. |
Type Of Material | Database/Collection of data |
Year Produced | 2016 |
Provided To Others? | Yes |
Description | Adjuvants study-FMD vaccine at Indian Immunologicals |
Organisation | Indian Immunologicals Ltd |
Country | India |
Sector | Private |
PI Contribution | Conducted screening of 8 adjuvants with FMD vaccine in cattle and analyse the samples originated from the experiments. 4 selected adjuvants were tested in cattle at the Pirbright Institute and TLR III adjuvant was found as the best one. Under Follow on grant 12 cattle were vaccinated with existing vaccine with oil adjuvant and 12 cattle were vaccinated with oil and TLR III adjuvants. The protective immununity was assessed from the virus neutralizing antibody status. By 6 months post-vaccination only 17% of cattle were having protective antibodies (1:45 dilution) in conventional vaccine group whereas 80% cattle were having protective neutralizing titer (1:45) in TLR adjuvanted group. Therefore it is clear that adding TLR adjuvant one can increase the duration of immunity up to 6 months. |
Collaborator Contribution | Facilitate the animal experiments at their High containment |
Impact | Conducted screening of 8 adjuvants with FMD vaccine in cattle and analyse the samples originated from the experiments. 4 selected adjuvants were tested in cattle at the Pirbright Institute and TLR III adjuvant was found as the best one. Under Follow on grant 12 cattle were vaccinated with existing vaccine with oil adjuvant and 12 cattle were vaccinated with oil and TLR III adjuvants. The protective immununity was assessed from the virus neutralizing antibody status. By 6 months post-vaccination only 17% of cattle were having protective antibodies (1:45 dilution) in conventional vaccine group whereas 80% cattle were having protective neutralizing titer (1:45) in TLR adjuvanted group. Therefore it is clear that adding TLR adjuvant one can increase the duration of immunity up to 6 months. |
Start Year | 2016 |
Description | Epitope prediction for FMD and serosurvey in East Africa |
Organisation | University of Glasgow |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | 1. Vaccine strain selection for O and A serotype for East Africa. 2. Epitope mapping.3. Analysis of sample collected from Tanzania national parks and domestic animals |
Collaborator Contribution | 1. Establishing mathematical modelling correlating phenotype to genotype circulating viruses against existing antisera. 2. Sero-survey in wildlife and domesticated animals for epidemiological studies. |
Impact | 1. Vaccine strains were selected for O and A serotypes for FMD for East Africa. 2. Hotspots were detected for FMD prevalence |
Start Year | 2016 |
Description | Vaccine strain selction |
Organisation | Onderstepoort Veterinary Institute |
Country | South Africa |
Sector | Academic/University |
PI Contribution | 1. Vaccine strain selection for serotype O and A |
Collaborator Contribution | Vaccine strain selection for serotype SAT1 and SAT2 |
Impact | Vaccine strain for FMD serotype O and A were selected. |
Start Year | 2012 |
Description | 2 FMD workshop in Arusha, Tanzania |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | FMD diagnosis, sample collection and control by vaccination had been discussed |
Year(s) Of Engagement Activity | 2013,2014 |
Description | BBSRC Impact case study |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Trainings, workshops and awareness provided on FMD among farmers at Arusha, Tanzania. |
Year(s) Of Engagement Activity | 2012 |
URL | https://bbsrc.ukri.org/documents/foot-and-mouth-in-africa-pdf/ |
Description | Delivered a lead talk at Indian Association of Vetrinary Microbiology and Immunology ( IAVMI) at IVRI, Bareilly on PPR and FMD control by vaccination- February 6-7th, 2020 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Delivered a lead talk at Indian Association of Vetrinary Microbiology and Immunology ( IAVMI) at IVRI, Bareilly on PPR and FMD control by vaccination- February 6-7th, 2020. Further attended the panel meeting with FMD vaccine producers and FMD scientists at PDFMD and IVRI Bangalore to recommend Govt of India for the future control of FMD. Suggested boosting of the first dose FMDV vaccinated animals which will stimulate the immunity up to the second biannual vaccination to avoid any window for infection. |
Year(s) Of Engagement Activity | 2020 |
Description | Delivered a lead talk on FMD vaccine and chaired a scientific session at Indian Veterinary Association at New Delhi ( 25.7.19-28.07.19) |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Delivered a lead talk on FMD vaccine and chaired a scientific session at Indian Veterinary Association at New Delhi ( 25.7.19-28.07.19). |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.indianveterinaryassociation.in/wp-content/uploads/2019/07/... |
Description | Invited lead talk at Indian Association of Veterinary Anatomists (IAVA), Orissa university of agriculture and Technology, 2017 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Study participants or study members |
Results and Impact | A talk has been delivered on new generation FMD and PPR vaccines |
Year(s) Of Engagement Activity | 2017 |
Description | Invited talk on Efficacy FMD vaccine using TLR adjuvants at NVRQS, South Korea |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Satya Parida was invited to deliver a talk on FMD vaccine using TLR adjuvants. Since 2010 South Korea is facing FMD outbreak and preparing themselves to prepare their own FMD Vaccine. As we have identified TLR 3 is a good adjuvant for stimulating humoral and cell-mediated response I received sparked questions and discussion afterwards. Recently I have received queries for providing details about the adjuvants so that they can include this adjuvant to their vaccine. |
Year(s) Of Engagement Activity | 2016 |
Description | Lead talk on current FMD vaccines and future perspectives at Eorpe Science congress, Budapest |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Described the efficacy of existing FMD vaccines in cattle, sheep and goats and future perspectives. This sparked questions and discussions. |
Year(s) Of Engagement Activity | 2018 |
Description | Oral presentation at EUFMD meeting, Burgo, Italy on Longer duration of Immunity of FMD vaccine |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Talk on duration immunity for FMD vaccine and how it can be double by adding a TLR3 adjuvant to the correct vaccine formulation. This sparked questions and discussion afterwards. vaccine industries were keen on this. |
Year(s) Of Engagement Activity | 2018 |