Engineering probiotics for mucosal vaccination: from the Escherichia coli Nissle 1917 paradigm to a translational vaccine platform

Mucosal vaccination is attracting renewed interest because many clinically relevant pathogens first encounter the host at gastrointestinal or respiratory surfaces, whereas most established vaccines are administered parenterally and are optimized primarily to induce systemic immunity. Engineered probiotics are emerging as living antigen-delivery vectors that may combine mucosal delivery, transient biological persistence, microbial immune signals, and programmable antigen presentation within a single platform. This strategy is particularly relevant to gastrointestinal vaccination, where access to gut-associated lymphoid tissue (GALT) may support local secretory IgA together with systemic responses. SARS-CoV-2 provides an informative experimental bridge because, despite its dominant respiratory manifestations, it can involve intestinal epithelial cells and gastrointestinal mucosal immunity. Using the pAIDA–Escherichia coli Nissle 1917 (EcN) system as a bounded proof of concept, this Perspective defines an integrated translational framework linking GALT-directed immune priming, effective mucosal antigen dose, genetic stability, chassis de-risking, biocontainment, manufacturing, potency, and post-administration clearance. We explicitly distinguish antigen delivery and immunogenicity from functional immunity, protection, and clinical efficacy, and identify the experiments required to advance probiotic-vectored mucosal vaccines toward clinically testable products.