Abstract
A lipopolysaccharide from Pantoea agglomerans (LPSpa) has been applied to various fields for human use as a Toll-like receptor 4 ligand and its safety has been confirmed. Here, we showed for the first time the application of LPSpa as an effective mucosal adjuvant for activating vaccine-induced antigen specific immune responses. Mice sublingually immunized with influenza vaccine (HA split vaccine) with LPSpa induced both HA-specific IgG (systemic) and IgA (mucosal) antibody responses, which led to a significant increase in survival rate against lethal influenza virus challenge compared with subcutaneous vaccination. After sublingual administration of ovalbumin with LPSpa, ovalbumin-specific mucosal IgA responses were induced at both mucosal surfaces close to the immunized site and at remote mucosal surfaces. Sublingual administration of LPSpa evoked local antigen-uptake by dendritic cells in cervical lymph nodes. LPSpa induced cytokine production and the maturation and proliferation of innate immune cells via Toll-like receptor 4 in dendritic cells. Collectively, these results suggest that LPSpa can be used as an effective mucosal adjuvant to stimulate and activate local innate immune cells to improve and enhance mucosal vaccine potency against various pathogens.
Highlights
Almost all environmental pathogens enter the body through mucosal surfaces including the respiratory, gastrointestinal, and genital tracts that act as the first line of defense
The hemagglutination inhibition (HI) assay showed the same tendency as enzyme-linked immunosorbent assay (ELISA), where both s.c. and s.l. immunization with lipopolysaccharide from Pantoea agglomerans (LPSpa) induced sufficient production of HI Abs (H1N1) in serum (Fig 1E)
High levels of long lasting HA-specific Abs (H1N1) were observed until 12 weeks after the final immunization (Fig 1C and 1D). These results demonstrate that s.l. immunization with LPSpa elicited both systemic IgG comparable to s.c. immunization and mucosal IgA responses, which were not induced by s.c. immunization
Summary
Almost all environmental pathogens enter the body through mucosal surfaces including the respiratory, gastrointestinal, and genital tracts that act as the first line of defense. The s.l. route has recently been demonstrated to be an attractive site for vaccination against various bacterial and viral diseases [6,7,8,9,10] because antigens are not exposed to degradation caused by gastrointestinal tract [11] and are prevented from being redirected to the central nervous system [12,13,14]. Sufficient immune responses that protect from infectious pathogens, especially at mucosal surfaces, can be enhanced by co-administration with adjuvants (immunostimulation). Some Toll-like receptor (TLR) ligands are potential mucosal adjuvants for HIV gp140 and tetanus toxoid [19]. These findings suggest that vaccination by the s.l. route with a suitable adjuvant is an attractive method for the administration of vaccines. Especially for s.l. vaccination, we have focused on substances already approved for human use
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