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 addressed
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 action,
cells were transfected in vitro with pATRex and this resulted in formation of insoluble intracellular aggregates and apoptotic
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 aggregationpromoting
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.
Keywords: Vaccine, adjuvant, DNA vaccine, apoptosis, molecular adjuvant, plasmid.
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