title: Monophosphoryl Lipid A Enhances Efficacy of a Francisella tularensis LVS-Catanionic Nanoparticle Subunit Vaccine against F. tularensis Schu S4 Challenge by Augmenting both Humoral and Cellular Immunity.
abstract: Francisella tularensis, a bacterial biothreat agent, has no approved vaccine in the United States. Previously, we showed that incorporating lysates from partially attenuatedF. tularensisLVS or fully virulentF. tularensisSchu S4 strains into catanionic surfactant vesicle (V) nanoparticles (LVS-V and Schu S4-V, respectively) protected fully againstF. tularensisLVS intraperitoneal (i.p.) challenge in mice. However, we achieved only partial protection againstF. tularensisSchu S4 intranasal (i.n.) challenge, even when employing heterologous prime-boost immunization strategies. We now extend these findings to show that both LVS-V and Schu S4-V immunization (i.p./i.p.) elicited similarly high titers of anti-F. tularensisIgG and that the titers could be further increased by adding monophosphoryl lipid A (MPL), a nontoxic Toll-like receptor 4 (TLR4) adjuvant that is included in several U.S. FDA-approved vaccines. LVS-V+MPL immune sera also detected moreF. tularensisantigens than LVS-V immune sera and, after passive transfer to naive mice, significantly delayed the time to death againstF. tularensisSchu S4 subcutaneous (s.c.) but not i.n. challenge. Active immunization with LVS-V+MPL (i.p./i.p.) also increased the frequency of gamma interferon (IFN-γ)-secreting activated helper T cells, IFN-γ production, and the ability of splenocytes to control intramacrophageF. tularensisLVS replicationex vivoActive LVS-V+MPL immunization via heterologous routes (i.p./i.n.) significantly elevated IgA and IgG levels in bronchoalveolar lavage fluid and significantly enhanced protection against i.n.F. tularensisSchu S4 challenge (to ∼60%). These data represent a significant step in the development of a subunit vaccine against the highly virulent type A strains.
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Katharina
authors.initials: K
authors.lastname: Richard
authors.affiliation: Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Mann
authors.affiliation: Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Aiping
authors.initials: A
authors.lastname: Qin
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Barry
authors.affiliation: Department of Microbial Pathogenesis, University of Maryland School of Dentistry, Baltimore, Maryland, USA.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Ernst
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA svogel@som.umaryland.edu.
authors.forename: Stefanie N
authors.initials: SN
authors.lastname: Vogel
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D001428:Bacterial Vaccines / Q000008:administration & dosage / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004195:Disease Models, Animal; D005260:Female; D005604:Francisella tularensis / Q000276:immunology*; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D007070:Immunoglobulin A / Q000032:analysis; D007074:Immunoglobulin G / Q000032:analysis; D007371:Interferon-gamma / Q000378:metabolism; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives*; D008264:Macrophages / Q000276:immunology; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology; D014406:Tularemia / Q000276:immunology / Q000517:prevention & control*; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D001428:Bacterial Vaccines; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D008050:Lipid A; D022223:Vaccines, Subunit; D007371:Interferon-gamma; C048436:monophosphoryl lipid A
keywords: Francisella tularensis; LVS; Schu S4; catanionic surfactant; immunization; mice; monophosphoryl lipid A; nanoparticle; subunit vaccine; tularemia