Mucosal immunization with the Lung Lactobacillus-Derived Amphiphilic Exopolysaccharide adjuvanted recombinant vaccine improved protection against P. aeruginosa infection

Abstract

Abstract Respiratory infections caused by P. aeruginosa are a major health problem globally. The only therapeutic strategy against P. aeruginosa-induced infections, to date, is antibiotic treatment. A protective vaccine is urgently needed in view of the emergence of antibiotic-resistant strains associated with high-mortality cases; however, traditional vaccines are applied parenterally with adjuvants meant to induce a powerful serotype-dependent response which often fail to drive mucosal immune protection. Therefore, the development of vaccines targeting localized mucosal and disseminated systemic immune responses may represent a promising avenue for future research on P. aeruginosa vaccination. In this study, we investigated the lung microbiota-Lactobacillus plantarum WXD301-derived exopolysaccharide with excellent self-assembly properties that enable the formation of a homogeneous nanovaccine when encapsulating model antigens. Importantly, the delivery system effectively penetrated the nasal mucous layer and prolonged antigen retention. We subsequently developed a nano-P. aeruginosa vaccine candidate, EPS301@rPcrV, which provided effective and sustained protection against P. aeruginosa pneumonia that surpassed the durability achieved with the "gold standard" cholera toxin as an adjuvant. The EPS301-adjuvanted vaccine formulation elicited robust mucosal IgA and Th17/γδ17 T cell responses, surpassing those induced by the CTB-adjuvanted vaccination. Notably, these responses were sustained for a duration exceeding 112 days. Adoptive transfer experiments revealed that pulmonary CD4 T cells and γδ T cells, rather than humoral immunity, played an indispensable role in conferring protection against pneumonic P. aeruginosa infection following EPS301 adjuvanted vaccination. Intriguingly, IL-17A knockout mice exhibited lower survival rates, impaired bacterial clearance ability, and exacerbated lung tissue damage upon EPS301 adjuvanted vaccination against P. aeruginosa-induced pneumonia, indicating an IL-17A-dependent mechanism of action. In conclusion, our findings provided direct evidence that EPS301@rPcrV vaccine is a promising candidate for future clinical application against P. aeruginosa-induced pulmonary infection.