Manipulating systemic and mucosal immune responses with skin-deliverable adjuvants

Most medically important bacterial and viral pathogens gain entry into the body either via the skin or a mucosal surface. Vaccination provides a viable and cost-effective strategy for the prevention of such diseases and it has always been a principal aim with vaccinologists, to be able to promote simultaneously, protective immune responses both systemically and at mucosal surfaces. The paradigm that mucosal immunity is best stimulated by exposure to antigen via a mucosal route simply because inductive sites such as Peyer's patches and bronchial associated lymphoid tissues are located in the mucosal epithelium, has promoted a plethora of immunizing strategies aimed at delivering both antigen and adjuvant to mucosal surfaces. We have developed a novel adjuvant system capable of intradermal delivery of antigens complexed in an ISCOSOME delivery vehicle. This adjuvant, referred to as a skin and mucosal adjuvant or SAMA4, was efficacious in eliciting both systemic and mucosal IgG and IgA antibodies in sheep, pigs and mice. SAMA4 does not induce granulomatous lesions at the site of vaccine delivery and can be used to deliver adjuvanted antigens by other routes including intranasal, oral and intravaginal. Using ovalbumin as a test antigen, intradermally delivered ovalbumin-SAMA4 complexes was found to be very effective in promoting a cytotoxic T cell response. Attempts to dissect the mode of action of SAMA4 by flow cytometric analysis of lymphocyte populations from the spleen, lung, liver and thymus revealed an effect of route of vaccine delivery upon the composition of specific lymphocyte subsets in these various organ compartments. From this, it can be inferred that SAMA4 induced a route-dependent re-mobilization and alteration in lymphocyte trafficking patterns. Other mucosal adjuvants such as cholera toxin B and microspheres, when injected intradermally, tended to promote primarily, an IgG and not an IgA response against the carrier antigen.