title: A Francisella tularensis live vaccine strain that improves stimulation of antigen-presenting cells does not enhance vaccine efficacy.
abstract: Vaccination is a proven strategy to mitigate morbidity and mortality of infectious diseases. The methodology of identifying and testing new vaccine candidates could be improved with rational design and in vitro testing prior to animal experimentation. The tularemia vaccine, Francisella tularensis live vaccine strain (LVS), does not elicit complete protection against lethal challenge with a virulent type A Francisella strain. One factor that may contribute to this poor performance is limited stimulation of antigen-presenting cells. In this study, we examined whether the interaction of genetically modified LVS strains with human antigen-presenting cells correlated with effectiveness as tularemia vaccine candidates. Human dendritic cells infected with wild-type LVS secrete low levels of proinflammatory cytokines, fail to upregulate costimulatory molecules, and activate human T cells poorly in vitro. One LVS mutant, strain 13B47, stimulated higher levels of proinflammatory cytokines from dendritic cells and macrophages and increased costimulatory molecule expression on dendritic cells compared to wild type. Additionally, 13B47-infected dendritic cells activated T cells more efficiently than LVS-infected cells. A deletion allele of the same gene in LVS displayed similar in vitro characteristics, but vaccination with this strain did not improve survival after challenge with a virulent Francisella strain. In vivo, this mutant was attenuated for growth and did not stimulate T cell responses in the lung comparable to wild type. Therefore, stimulation of antigen-presenting cells in vitro was improved by genetic modification of LVS, but did not correlate with efficacy against challenge in vivo within this model system.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Deanna M
authors.initials: DM
authors.lastname: Schmitt
authors.forename: Dawn M
authors.initials: DM
authors.lastname: O'Dee
authors.forename: Joseph
authors.initials: J
authors.lastname: Horzempa
authors.forename: Paul E
authors.initials: PE
authors.lastname: Carlson
authors.forename: Brian C
authors.initials: BC
authors.lastname: Russo
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Bales
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Brown
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Nau
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D001428:Bacterial Vaccines / Q000008:administration & dosage*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D005260:Female; D005434:Flow Cytometry; D005604:Francisella tularensis / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D007114:Immunization; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D014406:Tularemia / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D014611:Vaccination; D014613:Vaccines, Attenuated / Q000008:administration & dosage*; D014774:Virulence
chemical_list: D001428:Bacterial Vaccines; D016207:Cytokines; D014613:Vaccines, Attenuated