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Periodic Report Summary 3 - TARGETFISH (Targeted disease prophylaxis in European fish farming)

Project Context and Objectives:
TargetFish advances the development of existing but insufficient and new prototype vaccines against socio-economically important viral or bacterial pathogens of Atlantic salmon, rainbow trout, common carp, sea bass, seabream and turbot. TargetFish will establish a generic knowledge-base for rational development of next generation fish vaccines and bring improved vaccines closer to application by addressing practical issues such as efficacy, safety and delivery route. To achieve these challenging tasks, we brought together 30 partners in a multidisciplinary consortium of RTD and SME partners that keep intensive communication with the vaccine and feed industries.
Traditionally, fish vaccines are based on inactivated bacteria or viruses. Next generation subunit vaccines use specific antigens produced in bulk culture. DNA vaccines administer a DNA sequence coding for the target antigen: the DNA is injected in the host, transcribed and the protein produced by the host itself. In WP1 ‘Antigens for vaccine development’, we provide antigens/DNA to optimize different types of fish vaccines. While some fish vaccines can be delivered by immersion, many require injection by hand, which is time-consuming. In WP2 ‘Development of novel mucosal delivery systems’, we address different delivery methods for fish vaccines, with oral delivery as most promising for mass vaccination. Adjuvants are required to ensure adequate protection by improving presentation of antigen. Water-in-oil emulsions of antigen and adjuvant often work efficiently but can trigger inflammation. Alternatively, molecular adjuvants; host messenger molecules or specific bacterial products, may improve protection without these side-effects. In WP3 ‘Adjuvants for improvement of fish vaccines’, we study the efficacy of new adjuvants for improved vaccination. The FP6-funded project Imaquanim has provided TargetFish with the most recent knowledge on the fish immune system. In WP4 ‘Dissection of protective immune responses’, we build on this knowledge to identify key elements that determine adaptive immunity, creating a scientific base for successful vaccination of fish. Three antibody types have been identified in fish: immunoglobulin (Ig)M, IgD and IgT. The induction of antigen-specific IgM in serum does not always correlate with protection; measuring IgT in mucosal tissues provides a new tool for the characterization of immune responses after oral or immersion vaccination. In WP5 ‘Monitoring vaccine efficacy’, we develop in vitro assays to analyze vaccine performance based on measuring all Ig types. Adjuvants may induce unwanted side-effects at the injection site. We aim to use improved oil-based adjuvants as harmless alternatives. DNA vaccines but also live attenuated vaccines can be highly efficacious, but safety concerns limit their use. In WP6 ‘Side effects and safety’, we aim to provide safety and efficacy data to facilitate future decision-making. Incomplete protection following vaccination may sometimes be due to suboptimal use of otherwise efficient vaccines. Management aspects such as suboptimal vaccination strategy in terms of prime-boost regimen may play a role. In WP7 ‘Optimising vaccination strategies to field conditions’, we address these issues by targeting practical aspects of fish vaccination.
The main objectives of Targetfish thus are to: 1) generate knowledge by studying antigens and adjuvants for different routes of administration while analyzing the underpinning protective immune mechanisms; 2) validate this knowledge with response assays for monitoring vaccine efficacy and safety, including issues associated to DNA vaccines; 3) approach implementation of prototype vaccines shortening the route to exploitation and 4) optimize vaccination strategies in order to obtain maximum protection in different sizes of fish.

Project Results:
In WP1 ‘Antigens for vaccine development’, we aim to provide antigens for the production of 1st, 2nd or 3rd generation fish vaccines. At M48 of the project all inactivated pathogens are available for further research in the other WPs and it has become clear that expression of recombinant antigens using yeast (Pichia pastoris), in particular, appears a highly promising protein expression method. This is especially true for viruses that form viral like particles. In contrast, phage-based vectors for delivery of DNA vaccines seem to have a low efficacy and live recombinant iridoviruses (ESV) appear to have a high virulency and thus the latter two methods do not seem optimal for vaccination purposes. In WP2 ‘Development of novel mucosal delivery systems’, we aimed to exploit different delivery methods for mucosal delivery of vaccine antigens prepared in WP1. The main results at M48 show that oral encapsulation by alginates can prevent antigen degradation and allow for antigen delivery and uptake in the intestine, thus providing a promising strategy for mucosal delivery af antigens. In WP3 ‘Adjuvants for improvement of fish vaccines’, we aim to study the efficacy of new or improved adjuvants. At M48 of the project, particular fish cytokines, next to commercially applied MontanideTM adjuvants appear promising adjuvants for injection vaccination. In WP4 ‘Dissect protective immune responses’, we aim to identify key elements that determine adaptive immunity in fish. At M48, samples from vaccinated (established, improved and new vaccins) and vaccinated-and-challenged groups have been analyzed for determination of protective immune responses using a scala of methods and tools developed to dissect systemic and mucosal immunity and protection conferred by injection or by oral and/or immersion route, for studies on all six major aquacultured fish species. Important for vaccination: antigen-specific memory B and T lymphocytes can persist for months after vaccination and are not drastically exhausted by a second vaccination In WP5 ‘Monitoring vaccine efficacy’, we aim to develop in vitro assays for measuring vaccine performance. At M48 of the project bath and co-habitation challenges have been developed successfully for all bacteria and viruses studied, allowing for the verification of efficacy of fish vaccines (established, improved and new vaccins) against these important fish pathogens. It appears that in vitro assays relying on the detection of specific mucosal Ig in mucus samples may not provide the best alternative to in vivo challenges because of low antigen-specific concentrations of these antibodies. Chemokine receptors, however, appear promising markers for vaccine efficiacy. In WP6 ‘Side effects and safety’, we aim to provide safety and efficacy data for future decision-making on 2nd and 3rd generation vaccines. At M48 of the project it appears that the commercially applied adjuvants positively selected in WP3 (MontanideTM) are safe for use in fish. The use of particular fish cytokines and/or fish pathogen-derived molecules as adjuvants for fish vaccines requires further confirmation of safety. Further, fate and persistence of plasmid-specific DNA is being scrutinized in host genomes, aiming to provide a scientific method to support the discussion on the safety of DNA vaccins. In WP7, ‘Optimising vaccination strategies to field conditions’, we aim to address practical aspects of fish vaccination, where improved methods for mass injection vaccination of young fish already provide the first successful results.
Potential Impact:
The aim of TargetFish is to reduce the present impact that fish diseases are having on the European aquaculture industry by advancing the development of existing (but not sufficient) and new prototype vaccines for Atlantic salmon (Salmo salar), rainbow trout (Oncorhynchus mykiss), common carp (Cyprinus carpio), sea bass (Dicentrarchus labrax), seabream (Sparus aurata), and turbot (Scophthalmus maximus). We have chosen to target a number of viral and bacterial pathogens defined as socio-economically important by the authorities in charge. Most often, these pathogens cause substantial mortalities and direct losses to the European aquaculture industry.
By bringing together a broad spectrum of fish pathologists and immunologists and by studying key pathways for the development of adaptive, protective immune responses, Targetfish aims to provide a generic knowledge base that will underpin the successful development of fish vaccines, now and in the future. Thereby we provide a long-lasting contribution to the prevention of important fish diseases in the European aquaculture industry. Thereby, as has been shown in Norway during the last 20 years upon the implementation of efficient fish vaccines, we expect to reduce impact of veterinary treatments on the environment.
Targetfish will contribute to the building of a European technological and knowledge platform of universities, research institutes and small-medium enterprises (SMEs), which finds its foundation in previously developed partnerships (e.g. FP6-funded initiatives such as Imaquanim), for a future improved immunity to infectious pathogens in the major aquaculture species in Europe. The international and multidisciplinary team of scientists that form Targetfish is well equipped to achieve the continued training of scientists with the aim to sustain the research area of fish vaccinology at its present competitive level but also the training of end-users such as fish farming, nutrition and
vaccine industry.
TargetFish has the ambition to demonstrate market applicability of a selected number of improved or new prototype vaccines. Via joint participation of its partners with representatives of nutrition and vaccine industry in an Industry Forum, Targetfish aims to drive prototype development in an industrial applicable way. This will facilitate adoption of new intellectual property and stimulate the presentation of new fish vaccines on the market. Thereby, TargetFish will increase the competitiveness of the aquaculture production sector, including vaccine producers, SMEs and fish farms.
In conclusion, TargetFish aims to (1) Improve/optimise the currently available vaccines/vaccination technologies, (2) Bring new vaccines/technologies closer to industrial application by improving efficacy, delivery and safety and (3) Establish a knowledge and technology baseline for development of next generation fish vaccines, now and in the future.

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