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: UNLISTED

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.

Publications

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Ludi AB (2014) Antigenic variation of foot-and-mouth disease virus serotype A. in The Journal of general virology

 
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.
3. We have demonstrated a potent TLR adjuvant that helps to stimulate FMD vaccine to provide both humoral and cell-mediated responses (CD4+ and CD8+) responses.
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.
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 they 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.
First Year Of Impact 2014
Sector Agriculture, Food and Drink,Communities and Social Services/Policy,Education,Healthcare,Manufacturing, including Industrial Biotechology
Impact Types Societal,Economic

 
Description Right FMD vaccine strains for East Africa. We have shown that existing serotype A vaccine is not working for East Africa where as better serotype O vaccines are availabe internationally for use. Government of all the East afican countries are aware about this from our publications. Further hot spots of FMD virus circulation in tanzania has been identifies through a PhD student collaborating to Glasgow University. We have shown that comination of existing oil adjuvant with TLR adjuvants provides better protection.
Geographic Reach Africa 
Policy Influence Type Gave evidence to a government review
URL https://www.pirbright.ac.uk/press-releases/2017/04/bbsrc-investment
 
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 05/2016 
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. 
 
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 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