Altres ajuts: Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA) RTA2012-00028-C02-02. This work was supported by grants from the Secretaría de Estado de Investigación, Desarrollo e Innovación to NR (AGL2012-33877), from Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria to EGF (RTA2012-00028-C02-02), and from Agència de Gestió d'Ajuts Universitaris i de Recerca to NR (2014 SGR-345) and AV (2014 SGR-132). Besides, the authors acknowledge the financial support granted to AV from the Centro de Investigación Biomédica en Red (CIBER) de Bioingeniería, Biomateriales y Nanomedicina financed by the Instituto de Salud Carlos III with assistance from the European Regional Development. DT thanks CONICYT-Chile for a PhD fellowship. NR is supported by Ramón y Cajal (RYC-2010-06210) fellowship. AV has been distinguished with an ICREA ACADEMIA Award.

The control of infectious diseases is a major current challenge in intensive aquaculture. Most commercial vaccines are based on live attenuated or inactivated pathogens that are usually combined with adjuvants, oil emulsions being as the most widely used for vaccination in aquaculture. Although effective, the use of these oil emulsions is plagued with important side effects. Thus, the development of alternative safer and cost-effective immunostimulants and adjuvants is highly desirable. Here we have explored the capacity of inclusion bodies produced in bacteria to immunostimulate and protect fish against bacterial infections. Bacterial inclusion bodies are highly stable, non-toxic protein-based biomaterials produced through fully scalable and low-cost bio-production processes. The present study shows that the composition and structured organization of inclusion body components (protein, lipopolysaccharide, peptidoglycan, DNA and RNA) make these protein biomaterials excellent immunomodulators able to generically protect fish against otherwise lethal bacterial challenges. The results obtained in this work provide evidence that their inherent nature makes bacterial inclusion bodies exceptionally attractive as immunostimulants and this opens the door to the future exploration of this biomaterial as an alternative adjuvant for vaccination purposes in veterinary.