title: Inclusion of Epitopes That Expand High-Avidity CD4+ T Cells Transforms Subprotective Vaccines to Efficacious Immunogens against Virulent Francisella tularensis.
abstract: T cells are the immunological cornerstone in host defense against infections by intracellular bacterial pathogens, such as virulent Francisella tularensis spp. tularensis (Ftt). The general paucity of novel vaccines for Ftt during the past 60 y can, in part, be attributed to the poor understanding of immune parameters required to survive infection. Thus, we developed a strategy utilizing classical immunological tools to elucidate requirements for effective adaptive immune responses directed against Ftt. Following generation of various Francisella strains expressing well-characterized lymphocytic choriomeningitis virus epitopes, we found that survival correlated with persistence of Ag-specific CD4(+) T cells. Function of these cells was confirmed in their ability to more effectively control Ftt replication in vitro. The importance of understanding the Ag-specific response was underscored by our observation that inclusion of an epitope that elicits high-avidity CD4(+) T cells converted a poorly protective vaccine to one that engenders 100% protection. Taken together, these data suggest that improved efficacy of current tularemia vaccine platforms will require targeting appropriate Ag-specific CD4(+) T cell responses and that elucidation of Francisella epitopes that elicit high-avidity CD4(+) T cell responses, specifically in humans, will be required for successful vaccine development.
authors.affiliation: Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840; and.
authors.forename: Lydia M
authors.initials: LM
authors.lastname: Roberts
authors.affiliation: Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840; and.
authors.forename: Deborah D
authors.initials: DD
authors.lastname: Crane
authors.affiliation: Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840; and.
authors.forename: Tara D
authors.initials: TD
authors.lastname: Wehrly
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Fletcher
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Jones
authors.affiliation: Immunity to Pulmonary Pathogens Section, Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840; and bosioc@niaid.nih.gov.
authors.forename: Catharine M
authors.initials: CM
authors.lastname: Bosio
mesh_terms: D000818:Animals; D001428:Bacterial Vaccines / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D005604:Francisella tularensis / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains
chemical_list: D001428:Bacterial Vaccines; D018984:Epitopes, T-Lymphocyte