Polyphosphazenes as Adjuvants for Animal Vaccines and Other Medical Applications

Abstract

Polyphosphazenes are a class of experimental adjuvants that have shown great versatility as vaccine adjuvants in many animal species ranging from laboratory rodents to large animal species. Their adjuvant activity has shown promising results with numerous viral and bacterial antigens, as well as with crude and purified antigens. Vaccines adjuvanted with polyphosphazenes can be delivered via systemic and mucosal administration including respiratory, oral, rectal, and intravaginal routes. Polyphosphazenes can be used in combination with other adjuvants, further enhancing immune responses to antigens. The mechanisms of action of polyphosphazenes have not fully been defined, but several systematic studies have suggested that they act primarily by activating innate immunity. In the present review, we will highlight progress in the development of polyphosphazenes as adjuvants in animals and their other medical applications.

Keywords: adjuvants; animals; bacteria; immunity; polyphosphazenes; vaccines; viruses.

Figure 1

Chemical structures of the polyphosphazene polymers PCEP and PCPP (reprinted from Mutwiri et al., , copyright 2007, with permission from Elsevier).

Figure 2

Proposed mechanism of action of PCEP: (1) PCEP injected into muscle is transiently retained locally, induces genes involved in innate immunity. (2) PCEP induces local cells to secret cytokines and chemokines. (3) The secreted cytokines and chemokines initiate recruitment of various immune cells, including APCs (such as DCs) to the injection site. The recruited cells are activated and secrete more cytokines and chemokines, which in turn chemoattracts other immune cells. All these events lead to formation of local immunocompetent environment at the injection site. (4) Recruited DCs (which express various PRRs both on the surface (TLRs, CLRs) and intracellularly (NLRs and RLRs) are recognized and/or activated by PCEP resulting in activation of inflammasome. It is not yet known whether PCEP modulates (5) Antigen uptake, process and presentation, or (6) maturation of APCs. (7) PCEP increases the trafficking of APCs to the draining lymph nodes to interact with antigen-specific B or T cell to (8) Resulting in potent antibody secreting B cells and/or effector CD8+ T cell responses. These events constitute adjuvant activity.

Figure 3

Immune responses to low dose of influenza virus X:31 antigen: IgG2a antibody responses were assayed in serum of BALB/c mice (n = 5 per group) given a single s.c. immunization with a low dose (0.2_g) of X:31 antigen alone, X:31 + alum, X:31 + PCPP or X:31 + PCEP. Each data point represents mean ± S.E.M. for titers as determined by ELISA. Groups with different letters are significantly different from each other (p < 0.05). Data are representative of two independent experiments (reprinted from Mutwiri et al., , Copyright 2007, with permission from Elsevier).

Figure 4

Serum HBsAg-specific IgG2a antibody titers in mice given a single SC immunization with a dose of 0.2 _g of HBsAg alone, HBsAg + PCEP, HBsAg + CpG or HBsAg + PCEP + CpG. Each data point represents mean ± S.E.M. of titers of anti-HBsAg as determined by ELISA. Groups with different letters are significantly different (p < 0.05) (reprinted from Mutwiri et al., , Copyright 2007, with permission from Elsevier).