title: Killed but metabolically active microbes: a new vaccine paradigm for eliciting effector T-cell responses and protective immunity.
abstract: We developed a new class of vaccines, based on killed but metabolically active (KBMA) bacteria, that simultaneously takes advantage of the potency of live vaccines and the safety of killed vaccines. We removed genes required for nucleotide excision repair (uvrAB), rendering microbial-based vaccines exquisitely sensitive to photochemical inactivation with psoralen and long-wavelength ultraviolet light. Colony formation of the nucleotide excision repair mutants was blocked by infrequent, randomly distributed psoralen crosslinks, but the bacterial population was able to express its genes, synthesize and secrete proteins. Using the intracellular pathogen Listeria monocytogenes as a model platform, recombinant psoralen-inactivated Lm DeltauvrAB vaccines induced potent CD4(+) and CD8(+) T-cell responses and protected mice against virus challenge in an infectious disease model and provided therapeutic benefit in a mouse cancer model. Microbial KBMA vaccines used either as a recombinant vaccine platform or as a modified form of the pathogen itself may have broad use for the treatment of infectious disease and cancer.
authors.affiliation: Cerus Corporation, 2411 Stanwell Drive, Concord, California 94520, USA.
authors.forename: D G
authors.initials: DG
authors.lastname: Brockstedt
authors.forename: K S
authors.initials: KS
authors.lastname: Bahjat
authors.forename: M A
authors.initials: MA
authors.lastname: Giedlin
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.forename: M
authors.initials: M
authors.lastname: Leong
authors.forename: W
authors.initials: W
authors.lastname: Luckett
authors.forename: Y
authors.initials: Y
authors.lastname: Gao
authors.forename: P
authors.initials: P
authors.lastname: Schnupf
authors.forename: D
authors.initials: D
authors.lastname: Kapadia
authors.forename: G
authors.initials: G
authors.lastname: Castro
authors.forename: J Y H
authors.initials: JY
authors.lastname: Lim
authors.forename: A
authors.initials: A
authors.lastname: Sampson-Johannes
authors.forename: A A
authors.initials: AA
authors.lastname: Herskovits
authors.forename: A
authors.initials: A
authors.lastname: Stassinopoulos
authors.forename: H G Archie
authors.initials: HG
authors.lastname: Bouwer
authors.forename: J E
authors.initials: JE
authors.lastname: Hearst
authors.forename: D A
authors.initials: DA
authors.lastname: Portnoy
authors.forename: D N
authors.initials: DN
authors.lastname: Cook
authors.forename: T W
authors.initials: TW
authors.lastname: Dubensky
mesh_terms: D000818:Animals; D001428:Bacterial Vaccines / Q000276:immunology*; D002250:Carbon Radioisotopes; D004260:DNA Repair / Q000235:genetics; D003713:Dendritic Cells; D004706:Endodeoxyribonucleases / Q000235:genetics; D029968:Escherichia coli Proteins / Q000235:genetics; D005363:Ficusin; D005434:Flow Cytometry; D007111:Immunity, Cellular / Q000276:immunology*; D008089:Listeria monocytogenes / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D014466:Ultraviolet Rays; D014611:Vaccination / Q000379:methods*
chemical_list: D001428:Bacterial Vaccines; D002250:Carbon Radioisotopes; D029968:Escherichia coli Proteins; D004706:Endodeoxyribonucleases; C036385:endodeoxyribonuclease uvrABC; D005363:Ficusin