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Vaccines against helminth infections

Final Report Summary - PARAVAC (Vaccines against helminth infections)

Executive Summary:
Livestock production efficiency is impaired by worm infections which are ubiquitous in grazing, livestock world-wide. Control is compromised by drug resistance. An alternative is vaccination and this project is developing vaccines to control several of the most important parasites.
The project has contributed to the development and commercial production of an effective native protein vaccine against Haemonchus contortus in sheep which has now been made available commercially in Australia and practical efficacy established in Brazil and South Africa, in the case of the latter, registration is in progress. Attempts to produce the vaccine in a recombinant form have, to date, failed but work indicates that this may be attributable to the glycan modifications to the proteins. The project has generated a highly effective prototype vaccine against Cooperia oncophora in cattle based on parasite secretions. A prototype recombinant vaccine has been developed and tested for the liver fluke Fasciola hepatica, in sheep and cattle, based on proteins isolated from parasite secretions with some success. Target proteins have also been identified in the bovine stomach worm Ostertagia ostertagi and a cocktail of recombinant proteins tested, again with considerable success. In the bovine lungworm, Dictyocaulus viviparus and the dog tapeworm Echinococcus granulosus, vaccine trials have been completed with variable success. In all cases, synthetic versions of these proteins have been produced in bacteria, yeast or in the free living nematode Caenorhabditis elegans as a prelude to commercial production. The project can be divided into:-
1. Defining vaccine efficacy with trials in both housed and grazing livestock
Computer models were developed to inform judging the likely performance of a vaccine in the field. The Haemonchus vaccine showed the required efficacy in a variety of trials globally. A cocktail of recombinant proteins, the content of which is based on proteomic definition of the native vaccine, has been produced but proved to be ineffective. The prototype vaccines against Cooperia oncophora and F. hepatica are also effective in the field. In the case of the former, previous trials were conducted with native protein and work has progressed on developing an effective recombinant version. For F. hepatica, the prototype vaccine is in recombinant protein form, is effective in housed trials and limited data to date indicate that the efficacy in the field would be adequate to control the disease. A large-scale field trial has been completed in Ireland with very encouraging results.
2. Defining the protective immune responses induced by these vaccines.
Work undertaken showed that the Haemonchus vaccine is antibody-mediated and a similar response mediates vaccine efficacy against lungworm in cattle.. In the case of Fasciola, work has focussed on how the parasite skews the host the host immune response. Considerable effort was expended to develop nanoparticle and bacterial biofilm technologies as vaccine delivery vehicles directly to the intestinal mucosa for the purpose of vaccination against Echinococcus granulosus in dogs.
3. Knowledge exchange/dissemination to policy makers, scientists, government departments and the general public.
This was addressed by interacting closely with the animal health industry, farmer organisations and other stakeholders to define required vaccine characteristics. The consortium addressed key issues associated with commercialisation such as the potential market uptake for a vaccine and the regulatory requirements for approval for sale. In addition, the outputs from Paravac to date are in the process of being submitted to peer-reviewed science journals, this providing independent quality control.
4. Training and knowledge exchange - includes participation in training programmes, staff exchanges and web site provision.
Training workshops were held on bioinformatics, immunohistochemistry, helminth immune responses and commercialisation. In addition, there have been staff and technical exchanges between the participants, for example in the area of recombinant protein production and the execution of vaccine trials. The project website http://www.paravac.eu/index.php is being updated.

Project Context and Objectives:
KBBE.2010.1.3-01 Development of vaccines and improvement of detection systems to control helminth parasite infections of livestock and reservoirs – SICA
Proposal full title: Vaccines against helminth parasites of livestock of economic and/or public health significance
Proposal acronym: Paravac
Type of funding scheme: Collaborative Project (large-scale integrating project) for Specific Cooperation Actions Dedicated to International Cooperation.
Work programme topics addressed:
(if more than one, indicate their order of importance to the project)
1) Development and delivery of vaccines against the parasites of livestock of high economic and/or public health importance – specifically – gastrointestinal nematodes, lungworms, liver fluke, and Echinococcus granulosus
2) Characterisation of Protective Immune Responses to these parasites to inform vaccine delivery
3) Knowledge exchange and training of scientists and veterinarians in participating developing countries in the characterisation of immune responses, vaccine technology and application
4) Outreach to farming organisations and other stakeholder groups in both developed and developing participating countries with a view to paving the way for early adopters of new vaccine technology

PROJECT SUMMARY
Livestock production efficiency is impaired by worm infections which are ubiquitous in cattle, sheep and goats world-wide. These cause severely debilitating gastro-intestinal, respiratory or liver disorders, dependent on the infecting species. Control of these parasites relies almost exclusively on the use of drugs, a solution threatened by the global emergence of worm strains which are no longer affected by these chemicals. An alternative, greener and more sustainable approach is to control these infestations by vaccination, but, with one exception, there are no commercial vaccines available for any of these parasites. Members of the present consortium, with participants from EU and Switzerland, North and South America, Africa and including 3 SMEs and a one major animal health company, have collaborated to develop prototype vaccines with the efficacy predicted to control several of the most important of these livestock parasites as well the tapeworm Echinococcus granulosus in dogs, which can also cause fatal disease in man.
This proposal aimed to deliver at least one of these prototype vaccines to the point of uptake by the commercial sector or through government/philanthropic agencies. This goal was addressed by:-
1) Developing effective native or synthetic vaccines, the latter using novel, molecular expression systems.
2) Defining the protective immune responses induced by these vaccines to order to optimise the structure of the antigens and the method of their delivery.
3) Defining vaccine efficacy with trials in both housed and grazing livestock
4) Providing a platform for training and knowledge exchange which includes participation in training programmes, short exchanges of staff, workshops,and web site provision.
5) Interacting closely with computer modellers, the animal health industry, farmer organisations and other stakeholders to define required vaccine characteristics.
6) Knowledge exchange/dissemination to policy makers, scientists, government departments and the general public.

Project Results:
See attachment
Potential Impact:
The output from this proposal will lead towards the development of safe and efficacious vaccines as an alternative or complementary tool in the control, reduction and management of the most important helminth infections of livestock. Paravac has contributed to the development and launch of a commercial vaccine to control Haemonchus contortus in sheep, cattle and goats, the vaccines being effective in field vaccine trials in Australia, Brazil and South Africa as well as providing vaccine technology for a related project with similar outcomes in buffalo in India funded by DIFID/BBSRC. It includes the development of a vaccine against hydatid infection of dogs - a transmission blocking vaccine. Vaccine development in livestock is essential given the development and spread of drug resistant helminths which threaten sustainable livestock production at a time when global demand for livestock products is predicted to increase year on year. Vaccines should minimize the negative impact of helminth infection on production, improve the livelihood of livestock producers, reduce environmental contamination and, of vital importance, reduce the development of antihelmintic resistance. A highly effective native protein vaccine has been developed against Cooperia in cattle as well as a recombinant protein cocktail vaccine against Ostertagia, also in cattle In the case of Echinococcus, a vaccine effective in the canine intermediate host will greatly reduce infection in sheep and reduce transmission to man arising from the consumption of contaminated meat products. The outcome of early trials where nanoparticles have been used to deliver antigen directly to the enteric mucosa of dogs shows a lot of promise although more extensive trials are required to consolidate this conclusion. In the case of the liver fluke Fasciola hepatica, a recombinant protein vaccine has utility as a transmission blocking vaccine and reduces liver damage.
The scientific benefit of this programme has enhanced progression towards the development of practically useful monovalent, with the possibility of multivalent, antihelminth vaccines by demonstrating that infection control can be achieved by vaccination in the absence of any chemical interventions, an important outcome in the face of increasing drug resistance in the target parasite populations. This has large positive implications for sustainable livestock production globally and will enhance European competitiveness in the global market place. This goal is in line with the EU RTD framework programme objectives for Agriculture and Fisheries as well as the objectives of national government programmes across the EU.
Expected impacts listed in the work programme
The output from this proposal will lead towards the development of safe and efficacious vaccines as an alternative or complementary tool in the control, reduction and management of the most important helminth infections of livestock. It includes the development of a vaccine against hydatid infection of dogs - a transmission blocking vaccine. Vaccine deveIopment in livestock is essential given the development and spread of drug resistant helminths which threaten sustainable livestock production at a time when global demand for livestock products is predicted to increase year on year. Vaccines should minimize the negative impact of helminth infection on production, improve the livelihood of livestock producers, reduce environmental contamination and, of vital importance, reduce the development of anthelmintic resistance. In the case of Echinococcus, a vaccine effective in the canine intermediate host will greatly reduce infection in sheep and reduce transmission to man arising from the consumption of contaminated meat products.
Given that work in Paravac has demonstrated that vaccination is a practical option for the control of Cooperia oncophora, Haemonchus contortus and, in work preceding Paravac, Ostertagia ostertagia in the field as well as providing strong evidence that transmission blocking vaccination is feasible for Fasciola hepatica and Echinococcus granulosus, the scientific benefit of this programme will be progression towards the development of practically useful monovalent, with the possibility of multivalent, antihelminth vaccines. This goal is in line with the objectives of national government programmes across the EU.
High level impacts with potential EU policy impacts include:-
• Effective vaccination would have considerable export earning potential for the EU given that the annual global market for anthelmintics is several billion euros annually.
• Effective vaccination would greatly reduce, in the longer term eliminate, the development of anthelmintic resistance.
• Effective vaccination would avoid the potential problems of drug residues in meat products and possible detrimental environmental effects arising from inappropriate disposal. The elimination of these factors would have considerable economic benefits for EU livestock production.
• Control strategies based on vaccination would remove many of the grazing management contraints imposed by repeated anthelmintic usage enabling greater flexibility for pasture usage. There would be less frequent requirement to muster flocks/herds
• The output above has the potential to increase the area of pasture usable for livestock production, a medium term benefit that would help attain the increase in demand for livestock products predicted up to 2050.
• Helminth control by vaccination would reduce the exposure of stock workers to potentially harmful chemicals.
• Helminth control by vaccination would enhance animal health and welfare
• Increase the potential for adequate helminth control in the third world where management procedures are more extensive and the cost of frequent drug therapy is prohibitive.
• Helminth control increases production efficiency, reduces waste and has enormous potential in reducing harmful gaseous emissions, thus providing another set of tools to combat climate change.
• increasing competitiveness of the consortium as the world leading research group on helminth vaccines thereby strengthening the European research area,
• A European consortium incorporating the recognised experts in the field, offers great potential for a truly collaborative effort that will not be limited to just one host-parasite system but will have a major and generic impact on the global research field of animal and human helminth diseases.
• building a knowledge centre on the molecular basis of the parasite with the host immune system.
• Using this immunological platform to inform optimal vaccine delivery in a manner that is practical to ensure maximal uptake
• Providing an intellectual base for the training of future researchers and a framework for knowledge exchange for training in developing countries.

Innovative activities

The innovative character of the work proposed originated from the fact that the state of the art at the start of the project had to be improved significantly before proven vaccine candidates could be included in any commercially viable, stable helminth vaccine. This required:
• The development of methods to produce effective recombinant parasite products by the using novel approaches to antigen expression.
• Development of novel methods of antigen delivery.
• Relevance to the end user addressed by frequent knowledge exchange with livestock farmers, veterinarians, policy makers, government departments and the public.
• Improvement of this interaction by the use of classic and modern information technologies such as the consortium web-site and e-learning.
• Close interaction with a major global animal health company (Zoetis) and consortium members have existing research agreements with other animal health companies.

Solving third world problems in dealing with animal parasitic diseases

• As noted above, developing a vaccine will circumvent the need to use chemical drugs in the fight against parasitic disease. The cost of these drugs prohibits frequent therapy in large parts of the developing world. As a result, helminth infections cause high mortality and morbidity in ruminants in these regions. Therefore, smallholders in developing countries would greatly benefit from the availability of synthetic and stable vaccines, and in addition, the welfare of their animals would improve considerably. Technology developed in Paravac (native protein vaccination to control Haemonchus) was used to show that the approach is a feasible and inexpensive option for control of this parasite as well as a parasite affecting buffalo, Mecistocirrus digitatus, this being demonstrated in collaborative work between Participant 1 and TANUVAS in Chennai, Tamil Nadu, India. The latter parasite is important in regions of India and across South East Asia where buffalo are extensively used by small holder farmers as draft animals.

Enhancing European competitiveness

• The export value to the European Union of ruminant livestock averages EURO 2.3 billion annually. This market is dependent on guarantees of quality and safety. Whether exports are in the form of meat or added-value meat and dairy products, they will only be accepted in markets if produced to high standards ensuring freedom from zoonotic pathogens and from potentially harmful drug residues. Milk and meat products for use by European consumers must also adhere to the same high standards with respect to freedom from zoonotic pathogens and drug residues.
• This project will strengthen the impact of European Research by conducting pioneering work on economically important helminth diseases of livestock that can later be transferred to provide improved control of other parasitic diseases including major disease problems affecting man in developing countries.

Sustainable rural communities
• European Agriculture is undergoing rapid change, particularly in respect of decoupling and reduction of subsidies and increased emphasis on environmental impact. The number of full-time farmers in Europe is declining with the result that more efficient production methods are essential to ensure food supply meets anticipated demand. Sheep farming is barely above subsistence level in many of the less fertile regions of Europe and any novel control tools which can, cheaply, sustain production would have immense socioeconomic impact.

Societal Benefits
1. Food Safety and Quality
The work has shown that vaccination can be a practical alternative to the present anthelmintic-based control of the most intractable and costly helminth parasites of farm animals in Europe. In addition, the technology developed will be applied also in countries (INCO states) supplying meat and dairy products into European markets. Vaccination as a control method does not pose problems in terms of residues and the requirement to monitor them, as is the case for anthelmintic-based control. The project has provided a cohort of scientists trained in the science and technology relevant to these areas and these in turn will develop technologies for low input, sustainable agriculture and disease control for several new targets which may arise through climate change.

List of Websites:
http://www.paravac.eu/index.php
Contact: Prof Dave Knox, Moredun Research Institute, Bush Loan, Edinburgh EH26 0PZ Email. dave.knox@moredun.ac.uk