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Anticoccidial vaccine development: the importance of genetic diversity and delivery strategy

Reference	BB/H009337/2
Principal Investigator / Supervisor	Professor Fiona Tomley
Co-Investigators / Co-Supervisors	Professor Damer Blake, Dr DhinakarRaj Gopal, Dr Raghavendra Rao Jammi, Professor Raman Muthusamy, Dr Arni S.R. Srinivasa Rao, Dr Kumarasamy Thangaraj
Institution	Royal Veterinary College
Department	Comparative Biomedical Sciences CBS
Funding type	Research
Value (£)	867,142
Status	Completed
Type	Research Grant
Start date	27/09/2010
End date	26/03/2014
Duration	42 months

Abstract

Coccidiosis is a disease caused by the protozoan Eimeria species. Resistance has been detected among Eimeria field populations to every anticoccidial drug within one year of introduction. As novel vaccination strategies based upon small numbers of antigens become closer to reality it is clear that the Eimeria species could evolve under selection to evade vaccine-induced host immune responses. The scope for evasion will be determined by a series of variables including the (i) extent of naturally occurring genetic diversity, (ii) frequency of polyclonal infection in the field and (iii) rate of cross-fertilisation, none of which are known for the Eimeria species. In order to define these variables and inform the development of sustainable anticoccidial strategies with direct relevance to alleviating the cost of coccidiosis on the poor we will collect a panel of Eimeria field strains from nine states across India. These strains will be supplemented by Eimeria strains from around the world available through an extensive global network of contacts at IAH. Sequences orthologous to those that code for the most promising immunoprotective antigens discovered in lab studies at IAH will be identified from multiple Eimeria species. The prevalence of coding polymorphism will be determined from multiple Indian and international strains. Through expansion of the sequencing targets to a panel of ten genotyping loci per species the data generated will be used to characterise genetic diversity among Eimeria field populations and model the relevance of in vivo cross-fertilisation on population structure. Based on these data allele-specific qPCR will be developed to monitor field sample clonality and inform mathematical model construction. The in vivo immunogenicity of genotypically distinct strains will be determined and compared to single antigen vaccination strategies. Antigen delivery using transgenic Eimeria as a vehicle will be investigated.

Summary

Chickens are the most numerous livestock animals, with >50 billion reared annually. They are the livestock species most widely kept by the poorest people in the world, providing both dietary protein of animal origin and a currency for local marketing and trade. In many countries, including many parts of India, the role of women in backyard and traditional poultry production systems is crucial and diseases that compromise the health or survival of poultry impact on many of the poorest members of society. In India, coccidiosis is consistently ranked in the top three causes of bird mortality but vaccination is only rarely used in the organised sector and little control of any sort is applied in the unorganised sector. Coccidiosis is a devastating disease of poultry caused by protozoan parasites of the genus Eimeria, estimated to incur global costs in excess of £1.5 billion per annum and ranked in the top ten diseases of livestock based upon impact on the poor in South Asia. Cost-effective, multivalent recombinant vaccines are becoming a realistic prospect due to the identification of immunoprotective antigens and development of transfection technologies. However, genetic resistance to anticoccidial drugs can occur rapidly in the field and a similar fate could befall novel anticoccidial vaccines that rely on a small number of antigens if these are polymorphic and selectable. To predict the likely efficacy and longevity of such vaccines in the field it is important to know the prevalence of naturally-occurring genetic (antigenic) diversity, rate of multiple infections and frequency of genetic exchange between parasites. It is crucial also to have strong geographical networks in place, both for collecting parasites for laboratory studies and to ensure efficient dissemination, delivery and support of traditional and new diagnostics and therapeutics (drugs and vaccines) to the world's poorest rural economies. A small panel of immunoprotective parasite antigens has been identified in two Eimeria species. It is proposed to identify genes coding for equivalent antigens in other economically important Eimeria species and to sequence these genes from a panel of field strains collected across India, and from strains collected from other parts of the world (available through an extensive global network of contacts at IAH). In total, ten genomic regions will be sequenced from each Eimeria field strain, seven of which are hypothesised to encode antigens under immune selection and three 'housekeeping' or 'neutral' loci. Using this information genetic diversity and Eimeria field population structure will be investigated, providing data for the construction of mathematical models to predict the occurrence and relevance of cross-fertilisation during natural infection. Quantitative PCR targeting genetically distinct sub-populations within each Eimeria field population will be used to test and develop the early models. The identification of effective vaccine antigens is just one step towards a successful vaccine. Using genetically distinct Eimeria strains, protective immunity induced by infection will be compared with immune responses stimulated through vaccination with one or more test antigens delivered as a recombinant protein, DNA vaccine, or using a transgenic Eimeria line as a vehicle. Homologous and heterologous challenge systems will be characterised. Data generated will help predict the likely responses of Eimeria field populations to the introduction of novel vaccines with a view towards ensuring sustainable efficacy against all Eimeria species. The development of new cheaper anticoccidial vaccines will have a huge impact on commercial poultry production and has the potential to be used as a tool by governments in developing countries to minimise the impact of infectious diseases on poultry. The provision of free vaccination to the poorest sectors of society can have a massive impact on the alleviation of poverty.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Animal Health, Immunology, Microbiology
Research Priority	X – Research Priority information not available
Research Initiative	Combating Infectious Diseases of Livestock for International Development (CIDLID) [2009]
Funding Scheme	X – not Funded via a specific Funding Scheme

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