Development of DNA vaccines for patients following stem cell transplantation

Abstract

For intracellular tumour or infectious disease antigens, induction of a cytotoxic lymphocyte (CTL) response is desirable.  To optimise induction of CTL, a modified DNA fusion vaccine has been developed: the C-terminal domain of FrC was removed to delete competitive epitopes.  Epitope presentation was then enhanced by re-positioning the peptide sequence of interest to the C-terminus of the remaining FrC domain.  We have previously shown in murine models that this vaccine (pDOM.peptide) successfully induced CTLs specific for a chosen tumour peptide.  In order to test the operation of this design in the clinic, an epitope from human cytomegalovirus, NLVPMVATV was chosen.  We have previously shown in mice that the DNA vaccine p.DOM-NLVPMVATV can induce CTL specific for the naturally processed peptide.  As part of a phase I clinical trail we have now safely vaccinated 3 stem cell transplant donors.  Cellular and humoral immune responses were monitored following vaccination and the results are presented.

Finally, to gain more insight into the ability of the new vaccine design to induce significant levels of specific CTL, I have developed the DNA vaccine pDOM-GILGFVFTL.  This vaccine induced CTLs specific for the epitope which is immunodominant in the response of HLA-A0201 individuals to Influenza A virus.  These CTLs could lyse cells infected with influenza virus and showed some efficacy in protecting mice from challenge with a lethal dose of influenza A virus.

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