Liponanoparticular mRNA and DNA fish vaccines with immunomodulator adjuvants – LipoFishVac

Aquaculture has become critical for human food production, and is the fastest growing food production sector. It is threatened by multiple diseases especially those caused by viruses, for which there are no treatment available. The sustainable development of aquaculture therefore requires new vaccines against viral diseases. Although messenger RNA vaccines have recently become an integral part of the vaccine arsenal, mRNA vaccines for fish are still in their infancy. However, we just obtained a LipoNanoParticle (LNP)/mRNA vaccine against a carp virus based on the results of our previous ANR funding, FishRNAvax. This vaccine induces an effective protection with a low dose of mRNA. To optimize this first mRNA vaccine candidate, we propose to understand the mechanisms involved as the mRNA vaccine modes of action remain poorly understood, making it difficult to improve them. To this aim,we will focus on two fish diseases, st the Viral Hemorrhagic Septicemia virus – VHSV - in trout, and against the Spring viraemia of carp virus – SVCV - in carp. These two models correspond to notifiable diseases and target representative species of the two main groups of farmed fish, cyprinids and salmonids. Importantly, they allow a comparison with existing DNA vaccines that induce high protection and neutralising antibodies. The proposal aims at characterizing the immune responses, both innate and adaptive, looking for correlates of protection induced by LNP-mRNA vaccinesin carp, and trout, in order to optimize mRNA vaccine formulation with low amount of mRNA. Thus, we will analyse the biodistribution of LNP mRNA after vaccination, and how it can be modulated by three immunomodulators acting as adjuvants. Indeed, we hypothetize thatco-administration of LNP mRNA with micelles bringing TLR agonists will increase the quality and intensity of responses, and will improve their mucosal localization. In particular, we will characterize the effect of the induction of type I IFN at the site of injection, since it increases considerably the intensity of the response to DNA vaccine in Salmon, and leads to much better protection. We will also investigate the structure of the B/T cell responses induced LNP mRNA vaccines or by challenge in vaccinated fish, by Ig/TCR repertoire sequencing. Based on our previous work, we will determine the frequency of public components (present in all individuals) of adaptive responses induced LNP mRNA vaccines, in comparison to what we previously found after immunization with live attenuated vaccine. The consortium gathers four partners with complementary expertise in chemistry, molecular fish immunology and vaccinology, to optimize the nanoformulation of LNP mRNA vaccines and to explore the particularities of fish responses to these innovative vaccines. The recent development of mRNA vaccines against COVID19 has underscored the lack of knowledge about the characteristics of responses induced by such vaccines, either quality and duration, as well as about their biodistribution, and the importance of the doses to ensure strong efficacy. Beside developing optimized mRNA vaccine candidates for carp and trout, this project aims at providing basic knowledge of immune mechanisms to fish mRNA vaccines when packaged in a biodegradable nanocarrier platform. Furthermore, it will explore i) the importance of mRNA doses for ensuring strong protective capacity ii) the importance of co-administration of immunomodulators (TLR ligands) to increase long lasting immunity and mucosal immune responses. This knowledge will be instrumental to guide future developments and design of the next generation of fish mRNA vaccines.