Plasmids encoding protein aggregation domains act as molecular adjuvants for DNA vaccines

Melamia Capitani, Fadi Saade, Kristina M. Havas, Mauro Angeletti, Fabio Concetti, Dimitrios Agas, Maria G. Sabbieti, Antonio Concetti, Franco M. Venanzi, Nikolai Petrovsky

    Research output: Contribution to journalArticle

    7 Citations (Scopus)

    Abstract

    Background: DNA vaccines provide high tolerability and safety but commonly suffer from suboptimal immunogenicity. We previously reported that a plasmid vector (pATRex), encoding the DNA sequence for the von Willebrand I/A domain of the tumor endothelial marker-8 (TEM8) when given in combination with plasmid-encoded tumor antigens acted as a powerful molecular adjuvant enhancing immunity against breast and melanoma tumors. Aims: In the present study we ad- dressed two unsolved issues; would the adjuvant action of pATRex extend to a DNA vaccine against infectious disease and, if so, what is the mechanistic basis for pATRex adjuvant action? Results: Here we show in a murine malaria vaccine model that co-administration of pATRex potentiates antibody production elicited by an intramuscular injection of plasmid encoding Plasmodium yoelii merozoite surface protein 4/5 (PyMSP4/5). pATRex enhanced the B-cell response and induced increased IgG1 production consistent with TH2 polarization of the DNA vaccine response. To explore the mechanism of adjuvant ac- tion, cells were transfected in vitro with pATRex and this resulted in formation of insoluble intracellular aggregates and apop- totic cell death. Using a structural modeling approach we identified a short peptide sequence (α3-β4) within ATRex responsible for protein aggregation and confirmed that transfection of cells with plasmid encoding this self-assembling peptide similarly triggered intracellular aggregates, caspase activation and cell death. Conclusion: Plasmids encoding aggregation-promoting domains induce formation of insoluble intracellular aggregates that trigger caspase activation and apoptotic cell death leading to activation of the innate immune system thereby acting as genetic adjuvants.

    Original languageEnglish
    Pages (from-to)161-169
    Number of pages9
    JournalCurrent Gene Therapy
    Volume14
    Issue number3
    DOIs
    Publication statusPublished - 1 Jan 2014

    Keywords

    • Adjuvant
    • Apoptosis
    • DNA vaccine
    • Molecular adjuvant
    • Plasmid
    • Vaccine

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  • Cite this

    Capitani, M., Saade, F., Havas, K. M., Angeletti, M., Concetti, F., Agas, D., Sabbieti, M. G., Concetti, A., Venanzi, F. M., & Petrovsky, N. (2014). Plasmids encoding protein aggregation domains act as molecular adjuvants for DNA vaccines. Current Gene Therapy, 14(3), 161-169. https://doi.org/10.2174/1566523214666140509114838