"21-ICRAD" Nucleic NanoVaccines for Fish

Aquaculture is the fastest growing food production sector, but it is significantly constrained by infectious diseases. Impact of viral infections
on fish health and welfare is particularly strong, involving important economic losses, and only few vaccines are available. Therefore, it is of
paramount importance to develop new vaccines to prevent fish viral diseases for the development of a sustainable aquaculture.
Experimental DNA vaccines against fish viral infections have been developed, some providing high protection but they are injected and
cannot be easily administered to young fish. Importantly, several DNA vaccines have been recently made commercially available but remain
expensive. mRNA vaccines hold much hope, but they are just beginning to be tested in fish. In mammals, they often induce strong
responses and good protection. They appear to be fast to produce and safer than DNA vaccines as they should not integrate into host
genomes.
In this context, the NucNanoFish project proposes to establish a nucleic acid platform using biodegradable nanoparticles for efficient
delivery of vaccines, through intra-muscular (IM) or oral/immersion routes, against to well-known viral diseases of several
European farmed fish species. We have selected four different relevant host-pathogen models through cutting edge expertise of each
consortium's partner. NucNanoFish will design, produce and test DNA/mRNA nucleic acid vaccines loaded or not onto safe-by-design
LipoNanoParticles (LNP). LNP are based on a PLA/PLGA (Poly-Lactic/Glycolic Acid) core surrounded with a lipid corona. We hypothesize that
their efficient uptake by mucosa or the recruitment of Antigen Presenting Cells (APC) at the site of injection will favour a protective immune
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response at the portal of entry of each relevant virus. To achieve these goals, NucNanoFish has assembled a consortium of six partners, with
highly complementary expertise: one in nanodelivery of antigen and mRNA using LNP, four groups of fish immunovirologists / vaccinologists
and a biotech company in DNA production.

While vaccines against several important bacterial diseases have been extremely successful and have almost abolished antibiotic treatments in European aquaculture, efficient vaccines are still lacking for most viral diseases, for which no realistic treatments are available. Furthermore, inducing mucosal immunity (i.e. at portals of viral entry) is a key strategy to confer protection to vaccinated subjects and to inhibit transmission in the population (herd immunity). We propose here to use nucleic acids (DNA and mRNA) encoding envelope glycoproteins or capsid proteins as vaccine candidates, as such structural antigens are central in protective immunity. Indeed, for the four viruses selected in the project, we have strong evidence that envelope or capsid proteins are the best targets.
Why Nucleic acid vaccines? Fish DNA vaccines afford very high protection against a number of economically important viral diseases. They have been developed since the late 90s, and several are now authorized for commercial use in North America and Europe. (2). The mechanisms explaining the remarkable efficacy of fish DNA vaccines need to be better understood, as well as safety issues and the characteristics of the memory response (magnitude, specificity, duration, link with innate response).mRNA vaccines have a number of advantages over DNA vaccines (4), but their development in fish disease models has just started. Specifically, mRNA vaccines (both lipid-encapsulated or naked molecules) induce strong immune responses, and are suited for fast development, manufacture cost is affordable and administration is safer than DNA as there is very low risk of genome integration. Recent improvements of mRNA vaccines include stabilisation of the mRNA and improved delivery methods. However, there are still several factors to be overcome, including the profile of the immune response and the IFN responses that can perturb immunisation.