title: Increase in DNA vaccine efficacy by virosome delivery and co-expression of a cytolytic protein.
abstract: The potential of DNA vaccines has not been realised due to suboptimal delivery, poor antigen expression and the lack of localised inflammation, essential for antigen presentation and an effective immune response to the immunogen. Initially, we examined the delivery of a DNA vaccine encoding a model antigen, luciferase (LUC), to the respiratory tract of mice by encapsulation in a virosome. Virosomes that incorporated influenza virus haemagglutinin effectively delivered DNA to cells in the mouse respiratory tract and resulted in antigen expression and systemic and mucosal immune responses to the immunogen after an intranasal (IN) prime/intradermal (ID) boost regimen, whereas a multidose ID regimen only generated systemic immunity. We also examined systemic immune responses to LUC after ID vaccination with a DNA vaccine, which also encoded one of the several cytolytic or toxic proteins. Although the herpes simplex virus thymidine kinase, in the presence of the prodrug, ganciclovir, resulted in cell death, this failed to increase the humoral or cell-mediated immune responses. In contrast, the co-expression of LUC with the rotavirus non-structural protein 4 (NSP4) protein or a mutant form of mouse perforin, proteins which are directly cytolytic, resulted in increased LUC-specific humoral and cell-mediated immunity. On the other hand, co-expression of LUC with diphtheria toxin subunit A or overexpression of perforin or NSP4 resulted in a lower level of immunity. In summary, the efficacy of DNA vaccines can be improved by targeted IN delivery of DNA or by the induction of cell death in vaccine-targeted cells after ID delivery.
authors.affiliation: Discipline of Surgery, The University of Adelaide, Basil Hetzel Institute , Adelaide, South Australia, Australia.
authors.forename: Tessa
authors.initials: T
authors.lastname: Gargett
authors.affiliation: Discipline of Surgery, The University of Adelaide, Basil Hetzel Institute , Adelaide, South Australia, Australia.
authors.forename: Branka
authors.initials: B
authors.lastname: Grubor-Bauk
authors.affiliation: Division of Information Technology, Engineering and the Environment, School of Engineering, University of South Australia , Adelaide, South Australia, Australia.
authors.forename: Darren
authors.initials: D
authors.lastname: Miller
authors.affiliation: Discipline of Surgery, The University of Adelaide, Basil Hetzel Institute , Adelaide, South Australia, Australia.
authors.forename: Tamsin
authors.initials: T
authors.lastname: Garrod
authors.affiliation: Discipline of Surgery, The University of Adelaide, Basil Hetzel Institute , Adelaide, South Australia, Australia.
authors.forename: Stanley
authors.initials: S
authors.lastname: Yu
authors.affiliation: South Australian Health and Medical Research Institute, North Terrace , Adelaide, South Australia, Australia.
authors.forename: Steve
authors.initials: S
authors.lastname: Wesselingh
authors.affiliation: Inflammation Biology Laboratory, QIMR Berghofer Medical Research Institute , Brisbane, Queensland, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Suhrbier
authors.affiliation: Discipline of Surgery, The University of Adelaide, Basil Hetzel Institute , Adelaide, South Australia, Australia.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Gowans