Evaluation of the protective effect of the intranasal vaccines adjuvanted with bacterium-like particles against intestinal infection.

Mucosal vaccination presents a promising complement to parenteral vaccination. Bacterium-like particles (BLPs), peptidoglycan structures prepared from lactic acid bacteria, are explored as potential nasal vaccine adjuvants for respiratory infections. To date, studies on BLP-adjuvanted nasal vaccines against intestinal infections have remained limited. In this study, we demonstrated the efficacy of intranasal BLP-adjuvanted vaccination in controlling intestinal infections using the Citrobacter rodentium (C. rodentium) model in C57BL/6 mice. Intranasal vaccination of Intimin, an adhesin critical for intimate bacterial adhesion to colonic epithelial cells, combined with BLP (BLP+I) elicited robust Intimin-specific intestinal secretory IgA production, reduced bacterial load in feces and almost completely inhibited colonic hyperplasia, a characteristic symptom of C. rodentium infection in mice. Conversely, parenteral vaccination with Alhydrogel-adjuvanted Intimin failed to induce intestinal Intimin-specific IgA production, resulting in poor protection against C. rodentium infection. This underscores the pivotal role of mucosal IgA responses elicited by intranasal immunization in its protective efficacy. As this study did not delineate the precise protective mechanism conferred by BLP+I intranasal immunization against C. rodentium infection, further elucidation of the mechanisms underlying intranasal BLP+I immunization is required.

The adjuvant effect of bacterium-like particles depends on the route of administration.

Direct administration of vaccines to mucosal surfaces, such as via oral or nasal vaccination, represents an attractive alternative, or complement, to current parenteral vaccination because it has a potential to induce antigen-specific immunity both at mucosal and systemic tissues. Although bacterium-like particles (BLPs), peptidoglycan structures derived from lactic acid bacteria, have been investigated as a novel adjuvant for oral or nasal vaccines, it remains unclear whether the administration routes differ the adjuvant effect of BLPs. Here, we showed that the adjuvant effect of BLPs from Lactococcus lactis NZ9000 is greater with the nasal administration than with the oral administration. We conjugated BLPs with Tir, a virulence factor of Citrobacter rodentium, as a model adjuvant-antigen complex, and found that nasal, but not oral, immunization of mice with BLP-Tir induced robust antigen-specific IgA responses at the respiratory and intestinal mucosa, IgG2b-skewed systemic responses, and Th17 cellular responses. As one of the underlying mechanisms, we demonstrated that the nasal administration has a greater delivery efficiency (~1,000-fold) of the BLPs-conjugated antigens to mucosal-associated lymphoid tissues than the oral administration. Furthermore, the nasal, but not oral, administration of BLP-Tir elicited robust innate immune responses that were characterized by the expression of various pro-inflammatory cytokines and chemokines in the mucosal-associated lymphoid tissues. Considering these findings together, we anticipate that BLPs can be an attractive novel adjuvant for nasal vaccines targeting not only respiratory but also gastrointestinal infectious diseases.