An LNP-mRNA vaccine protects fish against rhabdovirus infection

mRNA vaccines are poised to revolutionize disease prevention, following the approval of their administration to humans against SARS-CoV-2. Although they have been extensively studied for human applications, their potential in the veterinary field has not been explored yet. No mRNA vaccines have yet been reported for fish, despite the urgent need for new vaccines against emerging pathogens in aquaculture. As fish are ectotherms, temperature has an impact on their immune response and on many other biological parameters, including the composition of membrane lipids. It is therefore crucial to identify whether mRNA delivery systems are suitable for in vivo expression in fish for vaccine purposes. In the present study, we developed a proof of concept for mRNA vaccination in rainbow trout, a salmonid, demonstrating the efficacy of current vaccine delivery systems in fish. We used lipid nanoparticles (LNPs), which represent the most advanced delivery technology for mRNA. LNPs use a combination of lipid components that form an encapsulating structure offering protection and promote endosome escape of the mRNA to allow its expression. In vitro assays showed that LNPs are a powerful vehicle for mRNA delivery in fish cells without substantial toxicity. In vivo imaging in adult zebrafish (Danio rerio) demonstrated that intramuscular injection of LNP-formulated egfp mRNA resulted in local expression of eGFP for up to 7 days. An LNP-based mRNA vaccine candidate encoding the viral haemorrhagic septicaemia virus (VHSV) glycoprotein induced neutralizing antibodies in rainbow trout (Oncorhynchus mykiss) and offers almost complete protection against a lethal viral challenge. Our data constitute a first proof of concept of mRNA vaccination in fish, paving the way for new developments in veterinary vaccines for aquaculture.