title: Apoptosis is essential for the increased efficacy of alphaviral replicase-based DNA vaccines.
abstract: Alphaviral replicons can increase the efficacy and immunogenicity of naked nucleic acid vaccines. To study the impact of apoptosis on this increased effectiveness, we co-delivered an anti-apoptotic gene (Bcl-X(L)) with the melanocyte/melanoma differentiation antigen TRP-1. Although cells co-transfected with Bcl-X(L) lived longer, produced more antigen and elicited increased antibody production in vivo, co-delivery of pro-survival Bcl-X(L) with antigen significantly reduced the ability of the replicase-based vaccine to protect against an aggressive tumor challenge. These data show for the first time that the induction of apoptotic cell death of transfected cells in vivo is required for the increased effectiveness of replicase-based vaccines. Our findings also provide an explanation for the paradoxical observation that replicase-based DNA vaccines are much more immunogenic than conventional constructs despite reduced antigen production.
authors.affiliation: Surgery Branch, National Cancer Institute, National Institutes of Health, Building 10, Room 2B42 Bethesda, MD 20892-1502, USA. wolfgang_leitner@nih.gov
authors.forename: Wolfgang W
authors.initials: WW
authors.lastname: Leitner
authors.forename: Leroy N
authors.initials: LN
authors.lastname: Hwang
authors.forename: Elke S
authors.initials: ES
authors.lastname: Bergmann-Leitner
authors.forename: Steven E
authors.initials: SE
authors.lastname: Finkelstein
authors.forename: Stephan
authors.initials: S
authors.lastname: Frank
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000032:analysis / Q000096:biosynthesis; D017209:Apoptosis / Q000276:immunology* / Q000502:physiology*; D019496:Cancer Vaccines / Q000276:immunology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D004247:DNA / Q000235:genetics / Q000276:immunology; D005434:Flow Cytometry; D008545:Melanoma / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010957:Plasmids / Q000235:genetics / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000276:immunology; D012093:Replicon; D012845:Sindbis Virus / Q000201:enzymology / Q000276:immunology; D014162:Transfection; D019444:Vaccines, DNA / Q000276:immunology*; D014765:Viral Vaccines / Q000276:immunology*; D051020:bcl-X Protein
chemical_list: D000914:Antibodies, Viral; C494812:Bcl2l1 protein, mouse; D019496:Cancer Vaccines; D019253:Proto-Oncogene Proteins c-bcl-2; D019444:Vaccines, DNA; D014765:Viral Vaccines; D051020:bcl-X Protein; D004247:DNA