title: The effect of stable macromolecular complexes of ionic polyphosphazene on HIV Gag antigen and on activation of human dendritic cells and presentation to T-cells.
abstract: Neonates and infants are susceptible to infection due to distinct immune responses in early life. Therefore, development of vaccine formulation and delivery systems capable of activating human newborn leukocytes is of global health importance. Poly[di(carboxylatophenoxy)phosphazene] (PCPP) belongs to a family of ionic synthetic polyphosphazene polyelectrolyte compounds that can form non-covalent interactions with protein antigens and demonstrate adjuvant activity in animals and in human clinical trials. However, little is known about their ability to activate human immune cells. In this study, we characterized the effects of PCPP alone or in combination with a model antigen (recombinant HIV-Gag (Gag)), on the maturation, activation and antigen presentation by human adult and newborn dendritic cells (DCs) in vitro. PCPP treatment induced DC activation as assessed by upregulation of co-stimulatory molecules and cytokine production. Studies benchmarking PCPP to Alum, the most commonly used vaccine adjuvant, demonstrated that both triggered cell death and release of danger signals in adult and newborn DCs. When complexed with Gag antigen, PCPP maintained its immunostimulatory characteristics while permitting internalization and presentation of Gag by DCs to HIV-Gag-specific CD4(+) T cell clones. The PCPP vaccine formulation outlined here has intrinsic adjuvant activity, can facilitate effective delivery of antigen to DCs, and may be advantageous for induction of beneficial T cell-mediated immunity. Moreover, polyphosphazenes can further reduce cost of vaccine production and distribution through their dose-sparing and antigen-stabilizing properties, thus potentially eliminating the need for cold chain distribution.
authors.affiliation: Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
authors.forename: Christine D
authors.initials: CD
authors.lastname: Palmer
authors.affiliation: Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
authors.forename: Jana
authors.initials: J
authors.lastname: Ninković
authors.affiliation: Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
authors.forename: Zofia M
authors.initials: ZM
authors.lastname: Prokopowicz
authors.affiliation: Boston Children's Hospital, Boston, MA, USA.
authors.forename: Christy J
authors.initials: CJ
authors.lastname: Mancuso
authors.affiliation: Apogee Technology Inc., Norwood, MA, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Marin
authors.affiliation: Apogee Technology Inc., Norwood, MA, USA.
authors.forename: Alexander K
authors.initials: AK
authors.lastname: Andrianov
authors.affiliation: Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Dowling
authors.affiliation: Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: ofer.levy@childrens.harvard.edu.
authors.forename: Ofer
authors.initials: O
authors.lastname: Levy
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000328:Adult; D000534:Alum Compounds / Q000494:pharmacology; D017951:Antigen Presentation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D007223:Infant; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D011108:Polymers / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000494:pharmacology*
chemical_list: D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D009943:Organophosphorus Compounds; D011108:Polymers; D011994:Recombinant Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; C108974:poly(phosphazene); C041524:aluminum sulfate
keywords: Adjuvant; Dendritic cell; Neonate; Newborn; T cell; Vaccine