Oral vaccination in fish: an updated overview and the case of Lactococcus garvieae

Aquaculture plays an increasingly central role in global animal food production, but infectious diseases represent a major constraint that compromises animal welfare, productivity, and the sustainability of the sector. Vaccination is widely recognized as one of the most effective preventive tools to control fish diseases and reduce reliance on antimicrobials. While injectable vaccines remain the gold standard in aquaculture due to their high and consistent efficacy, their application is limited due to labour requirements, handling stress, and impracticality in small fish and sea-cage systems. Oral vaccination represents the most attractive alternative, offering major advantages in terms of ease of administration, animal welfare, and suitability for mass immunization. This thesis provides an updated overview of oral vaccination in fish, focusing on the biological basis of mucosal immunity and the adaptive immune responses elicited following oral antigen delivery. The main constraints limiting oral vaccine efficacy, such as antigen degradation in the digestive tract, variable antigen uptake, oral tolerance, and incomplete understanding of mucosal immune correlates of protection, are discussed. Particular emphasis is placed on strategies to improve oral vaccine performance, including micro- and nano-encapsulation technologies, biological carriers, and the use of adjuvants, which collectively aim to protect antigens, enhance uptake by intestinal immune cells, and promote immunogenic rather than tolerogenic responses. The second part of the thesis focuses on fish lactococcosis, a globally important disease caused mainly by Lactococcus garvieae, which has recently expanded in both freshwater and marine aquaculture systems. Available experimental and commercial data on oral vaccines against lactococcosis are reviewed. Although primary oral vaccination alone generally induces variable and often suboptimal protection, encapsulated formulations and, especially, oral booster vaccination following primary parenteral immunization can significantly enhance and prolong protective immunity. Overall, this work highlights that oral vaccination is unlikely to replace injectable vaccines in the short term, but it represents a valuable complementary tool within vaccination strategies. Continued advances in fish immunology, formulation engineering, and standardized evaluation protocols are essential to unlock the full potential of oral vaccines and support their wider application, leading to more resilient, welfare-oriented, and sustainable aquaculture systems.