The Use of Irradiated Vaccines in the Control of Infectious Transboundary Diseases of Livestock

Closed for proposals

Project Type

Coordinated Research Project

Project Code

D32029

CRP

1730

Approved Date

20 October 2009

Status

4 - Closed

Start Date

11 June 2010

Expected End Date

11 June 2015

Completed Date

8 April 2016

Participating Countries

Argentina
Belgium
China
Ethiopia
Georgia
India
Iran (Islamic Republic of)
Kenya
Sri Lanka
Sudan
Thailand
Turkey
United Kingdom of Great Britain and Northern Ireland
United States of America

Description

Vaccination has been one of the greatest achievements of mankind in enabling the eradication of serious, life-threatening diseases of man and his domesticated livestock. Many of the vaccines used today rely on technologies developed over 100 years ago involving some form of attenuation, i.e. the use of an alternative or mutant strain of a pathogenic organism that has reduced virulence whilst maintaining immunogenicity, or inactivation, where chemical or physical methods are used to kill virulent pathogenic strains. Such vaccines have been extremely successful in protecting against diseases caused by viruses and bacteria in both animals and man. Amongst the success stories where control has been achieved can be included smallpox and Rinderpest, two diseases that had a global impact, but have now been eradicated.

Apart from their efficacy in improving animal health and productivity, vaccines can have another significant impact in a society that increasingly demands accountability from the farmer and food processor in relation to the livestock products they market. Regulatory agencies demand a reduction in the residues of veterinary pharmaceuticals in the food chain, and the use of antibiotics, or coccidiostats, has been severely curtailed in production systems in the EU. Also, as the vaccinated animals’ well-being is enhanced, the animal welfare lobby can be more readily appeased when intensive production methods are employed. Although the potential returns from veterinary vaccines is lower than that from human (even FMD vaccines enjoy a low market uptake) their importance will grow in the future as the need to increase productivity and livestock resources in the developing world to feed a growing population requires more effective control of emerging transboundary diseases (TBDs). For viral diseases this will be most important since there are only a few antiviral agents available and vaccination is the only effective way to avert infection. Although some conventional live and attenuated viral and bacterial vaccines are available not all livestock infectious diseases are covered and attempts are being made to develop subunit vaccines, live viral vector vaccines, DNA vaccines and gene-deleted vaccines.

Parasitic infections, including tick-borne diseases, animal trypanosomoses, and helminthoses also have a significant impact on productivity, not always by causing overt, clinical disease, but by their insidious impact leading to poor growth, low calving and reduced milk yield. Historically, chemotherapeutic drugs have been the mainstay of treatment and control of diseases caused by animal parasites. They have been viewed as cheap, safe and effective, although of course they are required to be constantly administered to ensure animals will thrive. Their greatest drawback has been in the emergence of drug resistance that reduces their efficacy, or prevents their use; in contrast, there is no evidence that similar genetic adaptation to vaccine-induced immunity ever occurs. With protozoal infections, a few vaccines have been produced based mainly on live parasites that result in a low level infection that stimulates a protective immune response similar to that produced by the natural infection. These methods include vaccination with low doses of infective organisms (Eimeria), infections controlled by chemotherapy (Theileria parva), attenuated vaccines (Babesia, Theileria annulata) or truncated life cycles (Toxoplasma).

Multicellular helminth parasites such as trematodes (e.g. Fasciola, Schistosoma), nematodes (e.g. Haemonchus) and cestodes (e.g. Taenia) present an even greater challenge to the development of suitable vaccines since they are large, complex multicellular organisms that, unlike smaller organisms, cannot be internalised by the hosts’ phagocytic immune mechanisms, but instead stimulate allergic type immune responses and the recruitment of leucocytes, mast cells and eosinophils. Not surprisingly, few vaccines have been developed to protect against infections with helminth parasites. There is however one commercially available vaccine, against the lungworm Dictyocaulus viviparus, consisting of radiation-attenuated, infective L3 larvae. In spite of the problematic issues in the production, batch-to-batch variation, storage and distribution of a live vaccine it has been used successfully for 50 years.

Nevertheless, research to develop other irradiated vaccines was not seriously pursued for the past twenty years due to two main reasons; firstly it was considered that the development of technologies was impractical or impossible and secondly that modern subunit vaccines would provide a solution as they could be more easily developed. Twenty five years on from the advent of recombinant technology and in spite of improved understanding in immune effector mechanisms involved in generating host immunity there has been little advance in recombinant vaccines for parasitic diseases. There is now good reason to re-evaluate the use of irradiation attenuation for vaccine production. The recent successful development of an irradiated vaccine for human malaria has demonstrated anew the feasibility and practicalities of this technique and indicated that technical problems can be overcome using existing knowledge without recourse to sophisticated technology.

This CRP is proposed for five years.

Objectives

Irradiation of pathogens was always thought as a way to prepare vaccines. Historically the killing by irradiation led to immunogens, which did rarely confer protection. So only when new irradiation tools were available (x-Ray, linear accelerators, e-beam) interest grew again in this technology. Advances in immunology showed that killed pathogens were not very immunogenic. This CRP set out to evaluate the irradiation of different pathogens to inhibit their capacity to replicate, but keep them metabolically alive. This entailed research into irradiation doses and procedures, protective additives and the development of tests to show and quantify metabolic activity. The specific objectives were to assess the efficacy of such radiation-attenuated vaccines and to determine how these technologies could be incorporated into a rational, targeted approach to identify strategies to develop irradiated vaccines for diseases of livestock where conventional vaccines are ineffective or unavailable. The goal was to assess which animal diseases would be the most appropriate pathogens to target in terms of their economic importance and the feasibility of developing a vaccine, to outline the approach and to assess the role of the Joint FAO/IAEA Division of Nuclear Techniques in Food and Agriculture in implementing a development programme.

Specific objectives

Develop a flow-through process for irradiating pathogens

Develop methods using isotope- and fluorescent-labelled parasites to enable tracking of parasites in vivo

Evaluate the cost benefits of radiation attenuated vaccines for Schistosoma bovis and F. gigantica

Evaluation of immune stimulation and dosage of irradiated pathogens

Evaluation of irradiation doses for various pathogens to render them replication incompetent

Evaluation of procedures to assay for metabolic activity in irradiated pathogens

Evaluation of protection conferred to by application of irradiated pathogens

Examine potential for enhancing production processes and improving the immunogenicity of RVF and Brucella vaccines by using radiation attenuation

Impact

This CRP had major impact in different ways:
1.) the interest in irradiated vaccine technology grew during the last 5 years, partly due to the scientific publications stemming from this CRP.
2.) 2 candidate vaccines were developed with a very good protection profile for parasitic diseases which could not be prevented before. An expert panel of immunologists applauded these findings as significant improvements
3.) Protocols and SOPs were developed to help the scientific community in progressing with irradiation technology for pathogen attenuation
4.) APH established an immunology laboratory in Seibersdorf to better address the technical needs of counterparts working on vaccine development or quality control.
5.) Farmers and the veterinary services in the MS will benefit from the achievements the most; First of all there is for the first time a proof of principle, that you can induce protection against Fasciola and Haemonchus infections with a simple, low tech solution. In economic terms this will reduce the costly "drenching" of livestock against parasites. Besides they are relatively simple to be produced, which makes them cheap and they are orally applied.
The Ichthyophthirius vaccine is as well the first tool to immunize fish against this fungus. And for this vaccine already a formulation for application is prepared and tested. This is good news for the fish hatcheries, as today they have to completely sanitize their premises if they have the fungus in their farms.
The brucella vaccine will offer for the first time and immunisation without a chronic infection of the vaccinated animals, as in the current life attenuated vaccines and thus will as well avoid the risk of contamination of the vaccinators.
6.) The proof of the concept of an irradiated vaccine conferring immunity and the basic protocols developed during the CRP opens the door to a new approach for emergency vaccines. Currently for instance in Theileria it takes ~ 200 passages of a field strain to render them fit as a vaccination tool, i.e. 2-3 years of work. with irradiation you can effectively take the infected animal, bleed it, culture the cells for a few days an after irradiation you can apply the vaccine. And as pone does not need to apply an antibiotic at the same time, costs are reduced as well.

Relevance

From the medical point of view, this CRP was extremely relevant as the molecular and proteomic approaches to develop novel vaccines for unmet needs did not yield any major success in the last 20 years. So irradiated vaccines show promising results. The 2nd important achievement was the proof, that irradiated but metabolically active pathogens can induce a solid immune response and protection.
And taken all these results together irradiation of pathogens could be the method of choice for the rapid development of a vaccines against an emerging disease. The fundamental irradiation protocols are developed and can be adjusted to other pathogens.

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