title: Effective polymer adjuvants for sustained delivery of protein subunit vaccines.
abstract: We have synthesized thermogelling cationic amphiphilic pentablock copolymers that have the potential to act as injectable vaccine carriers and adjuvants that can simultaneously provide sustained delivery and enhance the immunogenicity of released antigen. While these pentablock copolymers have shown efficacy in DNA delivery in past studies, the ability to deliver both DNA and protein for subunit vaccines using the same polymeric carrier can provide greater flexibility and efficacy. We demonstrate the ability of these pentablock copolymers, and the parent triblock Pluronic copolymers to slowly release structurally intact and antigenically stable protein antigens in vitro, create an antigen depot through long-term injection-site persistence and enhance the in vivo immune response to these antigens. We show release of the model protein antigen ovalbumin in vitro from the thermogelling block copolymers with the primary, secondary and tertiary structures of the released protein unchanged compared to the native protein, and its antigenicity preserved upon release. The block copolymers form a gel at physiological temperatures that serves as an antigenic depot and persists in vivo at the site of injection for over 50days. The pentablock copolymers show a significant fivefold enhancement in the immune response compared to soluble protein alone, even 6weeks after the administration, based on measurement of antibody titers. These results demonstrate the potential of these block copolymers hydrogels to persist for several weeks and sustain the release of antigen with minimal effects on protein stability and antigenicity; and their ability to be used simultaneously as a sustained delivery device as well as a subunit vaccine adjuvant platform.
authors.affiliation: Department of Chemical and Biological Engineering, Iowa State University, Ames, IA 50011, USA.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Adams
authors.affiliation: Department of Chemical and Biological Engineering, Iowa State University, Ames, IA 50011, USA.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Haughney
authors.affiliation: Department of Chemical and Biological Engineering, Iowa State University, Ames, IA 50011, USA. Electronic address: suryakm@iastate.edu.
authors.forename: Surya K
authors.initials: SK
authors.lastname: Mallapragada
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002942:Circular Dichroism; D003692:Delayed-Action Preparations; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005453:Fluorescence; D056724:Immunity, Humoral / Q000187:drug effects; D007114:Immunization; D008689:Methacrylates / Q000138:chemical synthesis / Q000737:chemistry; D008810:Mice, Inbred C57BL; D009757:Nylons / Q000138:chemical synthesis / Q000737:chemistry; D010047:Ovalbumin / Q000378:metabolism; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry*; D016062:Porosity; D055550:Protein Stability / Q000187:drug effects; D021122:Protein Subunits / Q000494:pharmacology*; D066244:Proton Magnetic Resonance Spectroscopy; D013056:Spectrophotometry, Ultraviolet; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000276:Adjuvants, Immunologic; D003692:Delayed-Action Preparations; D008689:Methacrylates; D009757:Nylons; D011108:Polymers; D021122:Protein Subunits; D022223:Vaccines, Subunit; C109846:poly(2-(diethylamino)ethyl methacrylate); D010047:Ovalbumin
keywords: Biocompatibility; Copolymer; Hydrogel; Immunochemistry; Pluronics