Activation of innate immune responses by a polyphosphazene adjuvant in pigs

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Adjuvants are substances which enhance immune responses to vaccines. To date, adjuvants have been used in billions of doses of vaccines for animals. Despite their extensive use, very little is known about how adjuvants work. This prompted one famous scientist to state that "adjuvants are the immunologist's dirty little secret". The lack of detailed understanding of how adjuvants work is a barrier to their rational use in vaccines. Furthermore, knowing how adjuvants work would alleviate some of the perceptions regarding their safety. **Available evidence suggests that most adjuvants, if not all, act by stimulating innate immunity which in turn directs the development of antigen-specific immunity (adaptive immunity). Numerous investigators have demonstrated that adjuvants influence various aspects of innate immunity including; the production of certain chemical mediators (cytokines and chemokines), recruitment of immune cells and the promotion of antigen transport to draining lymph nodes. **We have published extensively on the strong activity of a novel adjuvant, poly[di(sodiumcarboxylatoethylphenoxy)phosphazene] (PCEP), which is a synthetic biodegradable and water-soluble polyphosphazene polymer. We have shown that PCEP dramatically increases immune responses to a variety of experimental bacterial and viral vaccines. Most of these earlier studies were done in mice, but we have recently demonstrated that PCEP is a promising adjuvant in pigs, and we are currently exploring the potential of PCEP in improving swine influenza virus (SIV) vaccines for pigs in two other projects (see ongoing research support). However, no information is available on how PCEP works in pigs, which is a barrier to its rational use. Since most adjuvants act by stimulating innate immunity, we reasoned that investigating how PCEP activates innate immunity will provide valuable information on how this adjuvant works in pigs. In this regard, we propose to perform the following studies; 1): Assess the regulation of immune response genes induced by PCEP at the injection site, 2) Investigate the effect of PCEP on local and systemic cytokine and chemokine concentrations, 3)Identify the immune cells recruited at the injection site and in the draining lymph node, 4) Investigate activation of immune cells by PCEP in vitro, and 5) Assess whether retention of "antigen-adjuvant complex" (depot formation) at the injection site is required for adjuvant activity of PCEP.**Understanding how adjuvants work will provide valuable information on their rational use and also on their safety. Results from the proposed work will be a significant contribution to this end. In addition, the proposed studies will lay groundwork for similar studies with other adjuvants used in animal vaccines.